Journal of Computational Biophysics and Chemistry

Rabies, a neglected tropical disease, persists as a historical health challenge. The glycoprotein (G) gene of the rabies virus is the key antigen providing effective protection. Post-exposure prophylaxis involves vaccination and Rabies Immunoglobulins (RIGs) as per WHO guidelines. Identifying epitopes is crucial for specific immunotherapies. In this study, eight conserved epitopes were identified based on antigenicity, immunogenicity, MHC binding affinity, and IFN-$\gamma$ stimulation. A multiepitope vaccine was constructed and validated for antigenicity, stability, and safety. Protein–protein docking revealed RGP6 and RGP7 as strong candidates, with RGP6 showing the highest docking scores (–7.351 and –5.197) and potential as a novel target epitope for immunotherapy. The molecular dynamics simulations demonstrated that both 6LGX-ligand and 6LGW-ligand complexes maintained structural stability and dynamic equilibrium over the course of the simulation. Further, the binding free energy calculations for 6LGX (–79.440) and 6LGW (–47.338) suggest that the 6LGX-ligand complex is more stable than the 6LGW-ligand complex, as evidenced by their more negative values, indicating greater energy required for dissociation. The study suggests that the multi-epitope subunit vaccine is immunogenic, nonallergic, and capable of eliciting cellular and humoral immune responses.

Herein, we target LSD1 (KDM1A), a Lysine-specific demethylase enzyme responsible for demethylating the nucleosome’s mono- and di-methylated Histone proteins (H3K4/9), leading to epigenetic alterations in gene transcription. Growing evidence supports the involvement of LSD1 in Cancer and neurodegenerative diseases. Owing to the scarcity of clinically approved LSD1 inhibitors, we propose an alternate method to enhance LSD1 inhibitor repertoire by utilizing advanced computational techniques and logical multi-tier screening. In this work, we use a unique strategy via blending Structure-based pharmacophore (pharmacophore-S) and Ligand-based pharmacophore (pharmacophore-L) by employing common feature and Interaction-based pharmacophore mapping techniques to find novel hits against LSD1. The programs embedded with commercially purchased BIOVIA Discovery Studio Academic Research Suite were used for this purpose. The validated pharmacophores (pharmacophore-S and pharmacophore-L) were employed to screen InterBioscreen, COCONUT, and NCI natural compound databases based on fitting values of the candidates. The selected compounds were further screened using a multi-tier drug-likeness filtration based on Lipinski’s rule, Veber’s rules, SMARTS patterns, ADMET properties, and TOPKAT value. The funneled compounds were subjected to the molecular docking approach in the next round, and six compounds were chosen depending on the docking score and binding mode comparison with the reference. Then, MD simulation combined with MM-GBSA free energy binding calculations and Principal component analysis (PCA) were utilized to verify the stability of six compounds bound to LSD1. Overall, this study reveals the utilities of modern-day computational chemistry tools and uncovers four novel compounds as potential inhibitors of LSD1 for further studies.

Fused-ring electron acceptors (FREAs) have been pivotal in advancing the performance of organic solar cells (OSCs). However, challenges such as high production costs, synthetic complexity and limited scalability hinder their widespread industrial adoption. Nonfused-ring electron acceptors (NFREAs) present a promising alternative, offering more cost-effective and scalable photovoltaic solutions. Despite this, the power conversion efficiencies (PCEs) of NFREA-based OSCs still have significant potential for improvement. In this study, we explore the design of eight novel acceptor–donor–acceptor (A–D–A) NFREAs, referred to as TTS1–TTS8, achieved through end-group engineering of thieno[3,2-b]thiophene (TT) as the primary electron-donating unit, with 2,4,6-triisopropylphenyl (TIP) incorporated to provide steric hindrance. Density functional theory (DFT) and time-dependent DFT (TD-DFT) simulations provide insights into the impact of end-capping modifications on the photovoltaic properties of TTS1–TTS8. The optimization of these compounds through structural modifications has led to notable improvements in their photovoltaic performance. Among the developed series, the TTS8 compound exhibits a remarkable PCE of 17%, surpassing the theoretical limit of the reference molecule TTS-4F (12%). These molecules show increased binding energies ($\sim$0.299 eV), broadened absorption profiles (${\lambda }_{\text{max}}$ = 702–792 nm), reduced energy gaps (1.98–1.90 eV) and enhanced open-circuit voltages ($V_{\text{oc}}$ = 1.21–1.53 V). Further characterization through transition dipole moments (TDMs), electron density distributions (EDDs), molecular electrostatic potentials (MEPs), frontier molecular orbitals (FMOs) and reorganization energies (${\lambda }_h$ = 0.0061–0.0073 $E_h$, ${\lambda }_e$ = 0.0064–0.0076 $E_h)$ corroborates these improvements. Furthermore, the charge transfer analysis of TTS7/PM6 found a significant charge shifting at the HOMO (${\mathrm{\text{PM}}}_6)$ to LUMO (TTS7) interface. TTS8, in particular, stands out with its superior PCE, $V_{\text{oc}}$ of 1.53 V, 59% fill factor and excellent efficiency, making it a promising candidate for next-generation solar cell applications. These results highlight the potential of the TTS1–TTS8 series in advancing the development of high-performance and sustainable organic solar cells.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major respiratory disorder that is characterized by persistent airflow limitation and an abnormal inflammation response to noxious particles, such as cigarette smoke and environmental pollution. COPD is a leading cause of mortality, causing a significant economic and social burden in many countries worldwide. Umbelliferone, which is a coumarin derivative, has been shown to possess anti-inflammatory and antioxidant properties, which may be useful in alleviating COPD. METHODS: An integrative bioinformatics approach was adopted to analyze gene expression datasets from gene expression omnibus (GSE275503 for bulk RNA sequencing and GSE183974 for single-cell RNA sequencing). Differentially expressed genes (DEGs) were identified and overlapped with COPD-associated genes from GeneCards. Common genes were analyzed using the STRING database to construct a protein-protein interactions (PPI) network, and further processed in Cytoscape using the “cytoHubba” plug-in to identify the top 10 hub genes. Molecular docking of these genes, along with three key genes from single-cell analysis, was performed using AutoDock vina in SAMSON software. A molecular dynamic (MD) simulation study was carried out using Desmond and Schrodinger software. The MD simulations were performed to investigate the stability and dynamic behavior of the UMB with 6E3K and 1S9V over time 200 ns. RESULTS: From bulk and single-cell RNA sequencing analyses, 50 and 1053 DEGs were extracted, respectively, with the cut-off value of LogFC > 1 and $p$-value < 0.05. A total number of 562 overlapping genes were identified between the DEGs and COPD-associated genes from GeneCards. The top 10 hub genes from the PPI network were ITGAM, CCL2, IFN-$\gamma$, CCL5, FN1, IL-1B, BCL2, CDH1, IL-1A and CXCL8. Among these, molecular docking revealed the highest binding affinities for IFN-$\gamma$ (PDB ID: 6E3K, −7.4 kcal/mol), ITGAM (PDB ID: 1NA5, −6.6 kcal/mol), IL-1B (PDB ID: 8C3U, −6.2 kcal/mol), FN1 (PDB ID: 3M7P, −6.1 kcal/mol) and BCL2 (PDB ID: 6YLD, −5.9 kcal/mol). Additionally, single-cell RNA analysis identified HLA-DQA2 (PDB ID: 1H15, −2.7 kcal/mol), HLA-DRB5 (PDB ID: 1S9V, −4.9 kcal/mol) and S100A9 (PDB ID: 6ZDY, −5.3 kcal/mol) as the top three genes. An MD simulation study evaluated protein-ligand stability, binding dynamics and conformational changes. Root mean square deviation (RMSD) and Root mean square fluctuation (RMSF) analyses identified key interacting residues involved in hydrogen bonding, hydrophobic interactions and water bridges. The 6E3K complex exhibited protein backbone RMSD of 5−7 Å, ligand RMSD of 2−5 Å and residue fluctuations <3 Å. The 1S9V complex showed protein RMSD of 2.85 Å, ligand RMSD of 1.95−2.30 Å and residue fluctuations around 1.25−3.25 Å. CONCLUSION: The top 10 Genes from the PPI network and the top 3 genes from the single-cell RNA analysis were associated with COPD-related pathways. Molecular docking with the UMB showed strong binding affinities, indicating its potential to inhibit these pathways and serve as a therapeutic option for COPD. The MD simulation confirmed stable binding, key interactions and structural flexibility.

Gastroesophageal reflux disease (GERD) manifests in distinct phenotypes, including erosive reflux disease (ERD) and nonerosive reflux disease (NERD), which exhibit differences in pathophysiology and clinical outcomes. This study aims to explore microbial differences across these phenotypes. RNA sequencing data of 69 esophageal samples from reflux esophagitis (RE) and NERD patients were retrieved from NCBI SRA to identify key microbial taxa. Alpha and beta diversity analyses were conducted, and DESeq2 and Lefse analyses were used to identify bacterial biomarkers to differentiate ER from NERD. Five dominant phyla were identified, namely, Actinomycetota, Bacillota, Fusobacteriota, Pseudomonadota and Thermodesulfobacteriota. Genera such as Streptococcus, Fusobacterium and Phyllobacterium were abundant across the samples. Alpha diversity analysis revealed significant differences at the phylum, genus and species levels, with notable findings for Shannon, Chao1 and Simpson indices. Beta diversity analysis revealed significant differences in the microbial composition between ER and NERD at all taxonomic levels ($p$ < 0.001). DESeq2 analysis identified four phyla, 13 genera and 12 species with differential abundances between ER and NERD. Thermodesulfobacteriota and Actinomycetota were more abundant in NERD, whereas Pseudomonadota and Bacteroidota were higher in ER. At the species level, Acinetobacter baumannii and Escherichia coli were enriched in NERD, whereas Streptococcus mitis and Pseudoxanthomonas mexicana were elevated in ER. Lefse analysis identified potential bacterial biomarkers, with Thermodesulfobacteriota and Desulfomicrobium being significantly associated with NERD, whereas Fusobacteriota was linked to ER. Significant microbial differences were observed between ER and NERD, with distinct bacterial biomarkers identified. These findings suggest that the esophageal microbiota may play a role in the pathogenesis of reflux diseases, offering potential diagnostic and therapeutic targets. Further clinical research is needed to confirm these results and explore their clinical implications.

Nitrosourea (NU) and hydroxyurea (HU) are recognized as chemotherapeutic agents. Their efficiency is restricted by the risk of misuse and the release of trace amounts of un-metabolized chemicals into the environment. Numerous potential negative effects may arise from the use of these drugs. Nanomaterials for drug detection are essential in pharmaceutical research, particularly cancer therapeutic applications such as HU and NU. This study sought to investigate the sensitivity of the C${}_{24}$N${}_{24}$ nanocage in detecting HU and NU via density functional theory (DFT). The interactions between HU/NU drugs and the C${}_{24}$N${}_{24}$ nanocage were investigated using optimized geometries, adsorption energies, FMO, NCI, NBO and QTAIM analyses via DFT and TD-DFT at the B3LYP-D3/6-31G(d,p) theoretical level. The adsorption energy estimations of –24.47 kcal/mol for the NUG complex and –19.90 kcal/mol for the HUB complex indicate that the HU/NU medicines are strongly adsorbed onto the C${}_{24}$N${}_{24}$, and the process is exothermic. NCI and QTAIM analyses have shown noncovalent interactions, primarily van der Waals forces, between C${}_{24}$N${}_{24}$ and HU/NU drugs. When HU/NU interacts with the C${}_{24}$N${}_{24}$ surface, new energy levels are generated in the C${}_{24}$N${}_{24}$ PDOS. Upon evaluating the $E_{\text{g}}$ value, sensitivity and recovery time as parameters of the nanocage’s sensing efficacy, it was determined that the HUB complex exhibits the best conductivity (5.67 × 10${}^{12}$ S/m), fine sensitivity (0.2560) and most stability due to its small energy gap of 1.67 eV value. The complex NUG has the lowest recovery time with a value of 5.15 × 10${}^{-17}$ s. As a result of its recovery time, the C${}_{24}$N${}_{24}$ nanocage is highly desirable for its potential application as an HU/NU drug sensor. This demonstrates that HU/NU drugs can be efficiently identified by the C${}_{24}$N${}_{24}$ nanocage. Our findings indicate that the C24N24 nanocage may enhance drug detection (HU/NU), indicating possible pathways for further advancement.

In pre-antibiotic times, various highly contagious diseases like cholera, smallpox and tuberculosis were widespread worldwide. Penicillin discovery in the late 1920s was a groundbreaking moment in medical history, saving countless lives. However, over the next few decades, microbes developed antibiotic resistance, leading to a global public health threat known as antimicrobial resistance (AMR). Pseudomonas aeruginosa is a major contributor to hospital-acquired infections, affecting millions of patients and causing numerous deaths annually. Several non-$\beta$-lactam antibiotics combat these infections effectively, while their effect on P. aeruginosa quorum sensing (QS) has been insufficiently explored. We have undertaken comprehensive research to understand the effect of non-$\beta$-lactam antibiotics on various targets of P. aeruginosa. Using molecular simulations, we scrutinize these antibiotics” dynamic behavior and stability. Based on toxicity, binding energy and binding site, platensimycin and sulfasalazine were identified as promising candidates against various targets of P. aeruginosa. The binding energies for sulfasalazine and platensimycin with LasA were found to be −8.1 and −8.6 kcal/mol, respectively. Both of these leading antibiotics were interacting at the active sites of all tested proteins (LasA, LasI and PqsR). The examination of molecular dynamics confirmed the stable complex formation of the lead non-$\beta$-lactam antibiotics with all selected target proteins under normal physiological conditions. These findings emphasize the potential efficacy of platensimycin and sulfasalazine. They could potentially be repurposed for targeting the QS of P. aeruginosa.

Genus Fraxinusspecies has a long history in folk medicine worldwide, being utilized to address a wide array of pharmacological conditions, including anti-cancer, anti-diabetic, rheumatic pain, neuroprotective, immunosuppressive, anti-inflammatory and anti-obesity properties. Given the widespread regional application of Fraxinus for therapeutic purposes, this research, for the first time, explored the in vitro activities of F. hookeri fractions and analyzed their essential oil composition. The oils were analyzed by GC-MS for phytochemical composition. Cytotoxicity against Artemia salina and A-549 and HepG2 cell lines was assessed using the MTT assay. The antioxidant potential was evaluated with the DPPH assay and genotoxicity was tested on H2O2-induced DNA damage in human lymphocytes using the Comet assay. The compounds’ interactions with BCL2 and EGFR were determined using molecular docking. GC-MS analysis identified 12 bioactive phytochemicals, with linoleic acid ethyl ester (34.46%) being the most abundant, followed by 9,12-octadecadienoic acid (17.21%), $n$-Hexadecanoic acid (8.12%), hexadecanoic acid ethyl ester (7.41%). The MTT assay revealed significant growth inhibition of human hepatocellular and lung carcinoma cell lines, with IC50 values for FHNH at 113 ± 2.87 $\mu$g/mL and 120 ± 2.96 $\mu$g/mL. FHCF and FHNH showed high cytotoxicity against brine shrimps, with mortality rates of 80% and 73% at 1000 $\mu$g/mL, respectively. FHME demonstrated the highest DPPH scavenging ability (70.64 ± 3.03%). FHNH showed the highest protective efficacy against H₂O₂-induced DNA damage in lymphocytes, with significantly lower DNA damage (tail-DNA length 3 ± 0.54 $\mu$m) than control. $n$-Hexadecanoic acid and 9,12-Octadecadienoic acid were the best-docked ligands with BCL2 and EGFR. F. hookeri exhibits significant antioxidant, genotoxic and cytotoxic activities, making it a promising candidate for anticancer strategies and pharmacological applications. Its essential oils contain bioactive components valuable for nutraceuticals and biomedical uses.

The targeted delivery of therapeutic chimeric molecules significantly enhances pharmacological efficiency by triggering strong cellular uptake and prolonging the duration of systemic circulation. Purposeful molecular design incorporating specific chimeric protein–receptor interactions is an essential aspect of understanding biological mechanisms and precision modeling of molecular complexes. In this study, a detailed in-silico analysis was performed on a chimeric fusion protein designed to target Alzheimer’s disease. The fusion protein was created using the amino acid sequences retrieved from the beta-NGF, Nerve Growth Factor protein and the A$\beta$ peptide, with a rigid linker in place that ensures structural integrity. Its physicochemical characterization was predicted using ProtParam along with the evaluation of its secondary and tertiary structures, while its potential toxicity and allergenicity were analyzed through online analytical tools. The structural integrity of the fusion protein was evaluated through Rampage and ERRAT analyses, resulting in an ERRAT quality factor of 85 and indicating that 98.6% of the residues were placed within favored regions as suggested by the corresponding Ramachandran plot. Docking experiments were conducted using the HDOCK Server, followed by molecular simulations with the OpenMM engine, employing the AMBER force field for evaluation. The quality, validity, interaction analysis and stability of the fusion protein reveal that it indeed represents a functional molecular entity. The fact that the beta-NGF-A$\beta$ fusion gene is cloned and expressed in a suitable prokaryotic system may indicate that this is a very promising candidate for novel therapeutic approaches that target Alzheimer’s disease.

The ongoing COVID-19 pandemic has spurred international efforts to discover effective treatments against SARS-CoV-2. The essential oil (EO) of Algerian Origanum vulgare, which was extracted by steam distillation from aerial portions of the plant, contained a variety of bioactive substances that we were able to identify using a combination of gas chromatography–mass spectrometry and infrared spectroscopy (IR). The objective of this work is to ascertain this oil’s organoleptic and physicochemical characteristics. The drug interactions with important proteins involved in SARS-CoV-2 replication were evaluated using molecular docking studies. Certain compounds exhibited a strong affinity for binding, suggesting that they may have the ability to suppress viral activity. The stability and effectiveness of these interactions were validated by molecular dynamics simulations wherein carvacrol complexes demonstrated enhanced structural stability decreased flexibility compactness and decreased solvent exposure in contrast to other ligands. Both carvacrol and thymol are bioavailable and well absorbed according to ADMET analysis however there is a chance of skin irritation and liver toxicity. Carvacrol in particular showed minimal toxicity risks such as blockage of hERG or AMES low CNS permeability and slight long-term toxicity. These findings imply that Origanum vulgare essential oil might be a valuable natural resource for creating more effective COVID-19 treatments.

The recent surge in multi-drug-resistant organisms has led to millions of infections and deaths worldwide, highlighting the urgent need for novel antimicrobial agents. In response, this study aims to investigate the designed hybrid molecules of 1,3,4-oxadiazole-pyrazine derivatives (P1–15) and to assess their potential as DNA gyrase inhibitors through in silico approach. All the designed compounds were in compliance with Lipinski’s rule for drug-likeness, ADMET profile. Further molecular docking studies revealed that compounds P1 ($-6.94$ kcal/mol), P2 ($-6.50$ kcal/mol), demonstrated superior binding affinities, surpassing standard drug Novobiocin ($-5.79$ kcal/mol). The calculations related to MM-GBSA showed favorable free binding energy. A 200 ns MD simulations for P1 and standard Novobiocin were conducted to identify the key interactions occurring within the protein–ligand complexes. Based on these results, this study indicates that these compounds can be utilized to develop new antimicrobial agents by incorporating preferred structural modifications.

In this paper, we investigated the in silico molecular docking of 10 ligands relevant to wine tannins with 27 bitter taste receptors, TAS2Rs. A 3D superimposition analysis using TAS2R38 as the reference revealed that the majority of the remaining TAS2R proteins deviated from the reference structure within the 2-3 Å range, indicating moderate conformational shifts among them. We identified the protein–ligand binding site at the extracellular part and studied docking with the ligands associated with bitterness in wine tannins. Rigid-flexible molecular docking revealed protein-ligand binding affinities below the standard energy threshold (ΔG < –6.0 kcal/mol) for catechin, epicatechin, and flavan-3-ol, with a standard deviation of 0.5kcal/mol or less. These three ligands are relevant to the bitter taste of wine. Principal component analysis was used to determine the optimal mean number of clusters (n = 3). As a result, the TAS2R proteins are categorized into three distinct clusters on the basis of their ability to bind bitter ligands. This suggests that bitter taste forms a 2D space.

Organic solar cells (OSCs) have attracted significant interest from researchers due to their low cost, high-power conversion efficiency (PCE), and ability to compensate for light deficits. Four new acceptor molecules (CC1–CC4) have been designed. Several parameters have been studied including frontier molecular orbital (FMO), density of states (DOS), transition density matrix (TDM), reorganizational energies of electrons and holes, open circuit voltage ($V_{\text{o}\text{c}})$, and charge transfer analysis. The designed molecules (CC1–CC4) show promising optoelectronic features, with a narrower energy gap (0.320–1.922 eV) and absorption properties demonstrating that designed molecules exhibit ${\lambda }_{\text{m}\text{a}\text{x}}$ (560–698 nm). Excitation energy values range from 1.776 eV to 2.216 eV, which is lower for all of the developed compounds. This study will help researchers to design molecules for the development of efficient OSCs.

The major cause of death among men comes from prostate cancer which contributes a significant portion to the rate of mortality. The therapeutics including surgery, radiation, and chemotherapy, are often effective but can have an adverse side effect on the patient’s body. Numerous medicinal plants are available that contain therapeutic values to combat against cancer. The compounds of Eleusine coracana are known to possess numerous medicinal properties. Moreover, the plant is also known to possess promising anticancer effects. This work involved screening phytocompounds of E. coracana from the Indian medicinal plants database, IMPAAT, to investigate their ability as activators of HSP90AA1. The in silico tools, such as PASS Online server and pkCSM software were used to anticipate the anticancerous activity and ADMET properties, respectively. Molecular docking was used to determine the binding energies and validate the interaction between ligands and HSP90AA1. All the active substances, isovitexin, vitexin, triglochinin, caffeic acid and stigmasterol, have significant binding affinity for the HSP90AA1 binding pocket and demonstrate a suitable array of drug-like characteristics. Furthermore, MD simulation confirmed the protein-ligand complex’s stability, dynamic behavior and conformational changes. Taken together, isovitexin, vitexin, triglochinin, caffeic acid and stigmasterol might be used in designing potential drug molecules in targeting prostate cancer. Nonetheless, medicinal plants hold great potential in the development of novel, less toxic therapeutic agents for prostate cancer management.

The WNT10A gene, which codes for the WNT Family Member 10A (WNT-10a) protein and regulates WNT signaling pathways, has been linked to dental anomaly. WNT-10a protein binds with Frizzled (FZD (FZD1, FZD5 and FZD10) receptors and is involved in tooth development. Mutations in the WNT10A gene cause Oligodontia, tooth agenesis, microdontia and root maldevelopment by impairing WNT signaling. In addition, mutations in the WNT10A gene affect its structure and functional behavior of interaction with FZD receptors. However, the structural changes and interaction behavior of WNT-10 protein upon mutation at the molecular level are still unclear. Hence, in this study, the structural consequences of WNT-10a mutations at the atomic level were elucidated using a molecular simulation approach. Furthermore, docking simulations and MM-GBSA approaches were applied to investigate the interaction pattern of FZD proteins upon mutation in the WNT-10a protein. This study demonstrates that when the WNT-10a protein loses stability, the G213S mutant becomes more flexible, whereas R293C and T357I mutants become more rigid than the wild-type protein. This structural loss affects the interaction between WNT-10a and FZD1, FZD5 and FZD10 receptors which dysregulate the WNT signaling pathway in tooth development. Understanding this mechanism at a molecular level will be beneficial for treating dental anomalies.

Inflammation is a critical defense mechanism that mainly occurs in the human body through arachidonic acid metabolism and is needed to maintain a healthy life, but uncontrolled inflammation leads to several diseases like asthma, osteoarthritis, etc. Machilus macrantha is an important Indian medicinal plant that is traditionally used as an anti-inflammatory, anti-rheumatic agent but has yet to be explored much. Hence, this study has been undertaken to elucidate the molecular mechanisms underlying its anti-inflammatory activity by using network pharmacology and molecular modeling studies. Several free online tools and databases like SEA, Swiss target prediction, OMIM, GeneCards, Venny 2.1.0 and STRING were utilized to predict, compile and filter the anti-inflammatory targets and a total of 23 targets were obtained throughout the process. Further, by using the topology parameters (degree, betweenness and closeness) in Cytoscape 3.10.0 software, a total of five hub nodes or genes named PTGS2, NF$k\beta$1, MAPK1, CYP2C8 and CYP2C9 were identified which is mainly associated with arachidonic acid metabolism. KEGG and GO analyses were performed by using the SRplot tool and it was observed that arachidonic acid metabolism emerged as the top pathway with the lowest P-value and highest fold enrichment. The tissue enrichment studies of the hub genes were also performed using the Human eFP Browser. Finally, a ligand-target-pathway interaction network was created, which proved that the phytoconstituents of M. macrantha interact with multiple molecular targets of arachidonic acid metabolism and showed anti-inflammatory activity. Molecular docking and molecular dynamics simulation studies proved that a total of three ligands named machigline, machiline and quercetin exhibited moderate to good binding affinities toward the hub genes and machigline and quercetin showed stability in the binding cavity. From the present study, it can be concluded that the phytocompounds of M. macrantha have significant interactions with anti-inflammatory targets specifically on arachidonic acid metabolism, hence the same can act as an important source for developing novel anti-inflammatory agents.

Malaria, caused by Plasmodium parasites, remains life-threatening, with Plasmodium falciparum responsible for severe cases. The parasite’s invasion of Red Blood Cells (RBCs) is critical for infection. The interaction between Reticulocyte Binding Protein Homologue 5 (RH5), Basigin, monoclonal antibodies and Cysteine-Rich Protective Antigen (CyRPA) with glycan on RBCs is essential for this process. This study aims to identify small molecules inhibiting the RH5-CyRPA-RIPr invasion complex. A library of 2299 compounds from FDA-approved drugs and African natural products in the ZINC database was screened using molecular docking. Binding sites for Basigin, monoclonal antibodies and glycans on RH5 and CyRPA were targeted, with binding affinity cutoffs of −8.5 kcal/mol for monoclonal antibodies and −7.0 kcal/mol for CyRPA and Basigin. Compounds were assessed for pharmacokinetics, solubility, drug-likeness, lead-likeness and biological activity using the PASS online server. Molecular dynamics simulations and free energy calculations evaluated stability and binding efficiency. Nine hits for RH5 and three for CyRPA showed favorable stability and anti-protozoal activity (up to 0.65). African natural products exhibited similarities with drugs like Nequinate and Cyanidin, supporting further research. Promising small molecules were identified as potential inhibitors of P. falciparum invasion, laying a foundation for experimental validation and drug development.

Under hyperglycemic conditions, proteins undergo structural modifications non-enzymatically, resulting in the formation of advanced glycation end products (AGEs). These AGEs contribute to the production of free radicals, which in turn exacerbate the development of diabetes and its complications. Therefore, inhibiting glycation is anticipated to play a crucial role in managing diabetes. Here, we have examined the effect of 2-hydroxy-1,4-naphthoquinone (NQ) and silibinin on ribose-mediated glycation of HSA. Presence of NQ and silibinin inhibited the fluorescent AGEs formation by 79.18% and 84.10%, respectively. Moreover, the secondary structural loss caused by glycation was restored by NQ and silibinin treatment. Both the compounds showed higher affinity toward native HSA compared to glycated HSA as evident from their binding constants. Molecular docking showed a direct interaction of tested compounds with glycation prone amino acids arginine and lysine residues of HSA. Molecular simulation studies confirmed the NQ or silibinin formed stable complex with HSA. Both the ligands formed hydrogen bonds throughout the trajectory. MM-PBSA calculation showed the overall binding energies for silibinin and NQ with HSA were – 16.863 kcal/mol and – 9.977 kcal/mol, respectively. The findings show the antiglycation potential of NQ and silibinin against ribose mediated glycation of HSA along with mode of action.

Hepatocellular carcinoma, presenting a significant health challenge, requires innovative approaches for treatment and prevention. Therefore, this study aimed to comprehensively characterize the potential of compounds from Achillea arabica on the mTOR, Akt and ERK signaling pathways using in silico methods. The drug likeness and ADME/T properties of the compounds were investigated using online tools. Molecular docking and molecular dynamics simulations were used to examine the key interactions of the selected compounds with the mTOR, Akt and ERK target proteins along with the known inhibitors. Three phenolic compounds demonstrated a strong binding affinity as the top candidates. Compounds quercetin, luteolin and apigenin exhibit potential as nontoxic alternatives for hepatocellular carcinoma treatment, typically used as synthetic chemical inhibitors.

Novel nonlinear optical (NLO) molecules are designed in order to meet their tremendous demand in the field of optics and electronics. The first attempt of the structural tailoring of disperse orange 3 (DO3)-an azodye is made to develop nineteen derivative molecules (D1-D19). Two approaches were opted for preparing 4 groups of molecules. The first one was the extension of $\pi$-conjugated system and the second strategy was the use of diverse electron donor and acceptor groups to develop unique donor-$\pi$-acceptor systems. Density functional theory (DFT) calculations were performed for in silico characterization of the studied molecules. The polarizability (${\alpha }_o$) and first-order hyperpolarizability (${\beta }_o$) values gave the insight of nonlinear optical response. All the designed molecules with extended conjugation and unique electron donor and acceptor group combination showed remarkably high ${\alpha }_o$ and ${\beta }_o$ values. The highest hyperpolarizability value (42477.48 a.u.) with several thousand increases than ${\beta }_o$ (7113.25 a.u.) of reference DO3, was depicted by D19 of the designed derivatives. This can be attributed to greater intramolecular charge transfer (ICT) in it. Various interaction studies were made and global reactivity descriptors (GRDs) were calculated to determine their chemical nature and stability. The outcome of our study suggests that the designed molecules are potential candidates for NLO applications, like energy conversion for producing tunable lasers and high-resolution spectroscopic studies.

hERG channels regulate the heart’s action potential by controlling potassium ion flow during repolarization. This study analyzed 6362 molecules as potential hERG inhibitors using cheminformatics and machine learning, based on the hypothesis that molecular properties influence inhibition potency. We analyzed a dataset of 6362 molecules using cheminformatics and machine learning techniques to study properties such as hydrogen bond acceptors (nHA), topological polar surface area (TPSA), molecular weight (MW) and $c$Log$P$. Principal component analysis (PCA) and scaffold visualization were used to explore the molecular diversity and identify structural motifs. We developed 14 classification structure-activity relationship (CSAR) models with the Scikit-learn package, each validated through ten rounds of cross-validation. The Random Forest model’s performance was evaluated based on its accuracy across training, cross-validation and test sets. Potent hERG inhibitors typically had fewer nHAs and lower TPSA, with no consistent trend in MW. They also had slightly higher $c$Log$P$ values. PCA indicated an overlap between the potent and intermediate/inactive molecules, with less diversity in the potent group. The scaffold analysis identified five main cyclic skeleton systems (CSKs) among 144. The random forest model achieved accuracies of 0.987, 0.817 and 0.747 for the training, cross-validation, and test sets, respectively, effectively predicting hERG inhibition. The study found that specific molecular properties, lower nHA and TPSA, and higher cLogP are associated with potent hERG inhibitors. Identifying common structural motifs can aid in discovering new inhibitors, and the Random Forest model proved effective in classifying compounds based on their hERG inhibition activity.

The increasing prevalence of antimicrobial resistance, particularly in Gram-negative bacteria such as Acinetobacter baumannii, demands new antibiotics as existing ones become increasingly ineffective. The production of lipopolysaccharide (LPS) is vital in Gram-negative bacteria, making it a promising target for antibiotic development. This study focuses on discovering antibiotics targeting the early-stage LpxA, LpxC and LpxH enzymes. These are crucial to lipid A biosynthesis in the Raetz pathway and are vital for bacterial survival and virulence. LpxA transfers an R-3-hydroxy acyl chain during lipid A biosynthesis, crucial for bacterial growth and potential antibiotic development. Inhibiting LpxC can impede bacterial growth and increase vulnerability to other antibiotics, whereas targeting LpxH is especially lethal due to the buildup of toxic lipid A intermediates. We identified promising compounds using high-throughput virtual screening of 374 compounds from ChemDiv with Schrodinger’s Extra Precision (XP) mode, followed by MM-GBSA analysis. Molecular Dynamics Simulations (MDS) over 100 ns using GROMACS confirmed the structural stability of these proteins with novel lead compound complexes. Compounds with ChemDiv IDs N039-0003 and N002-0028 showed strong binding to LpxA, N034-0001 and N023-0006 to LpxC and N025-0038 and N039-0020 to LpxH, with binding energies between –4.85 kcal/mol and –8.41 kcal/mol and total binding energies spanning from –31.06 kcal/mol to –53.87 KJ/mol. These findings suggest that these novel lead compounds inhibit the LpxA, LpxC and LpxH proteins and serve as new antibiotics against A. baumannii. However, additional in vitro and in vivo studies are needed to confirm the efficacy of these compounds.

Prevotella copri is a prominent constituent of the human gastrointestinal microbiome, and its fluctuating abundance has been linked with positive and negative influences on diseases such as Parkinson’s disease and rheumatoid arthritis. Prevotella copri demonstrates flexibility against drugs. There is presently no vaccine approved by the FDA against prevotella copri,and treatment options are restricted. Hence, this research work was designed to create an in silico-based vaccine for prevotella copri.The protein sequences of two distinct strains ofprevotella copriwere retrieved from NCBI. The T-cell and B-cell epitopes were obtained and then analyzed for antigenicity, allergenicity, docking and simulation. The peptide comprises linear B-cell and T-cell epitopes from proteins identified as potential novel vaccine candidates. The molecular dynamics (MD) simulations and protein-protein docking results revealed that the vaccine exhibits strong and Sustained interaction with Toll-like receptor 4 (TLR4). The constructed sequence was integrated into the pET-30a (+) biological vehicle (vector) for subsequent analysis expression in E. coli through the SnapGene server. The constructed multi-epitopic vaccine candidate was assessed for its structural, physicochemical and immunological properties. The results demonstrated solubility, stability, antigenicity and nonallergenicity and showed a strong affinity for its target receptors. The in silico study represents a significant step forward in designing a vaccine that could effectively eliminate Prevotella copri globally.

Various tyrosine kinase inhibitors (TKIs) have been developed to target human epidermal growth factor receptor (EGFR) for cancer therapy. However, many patients treated with first-line TKIs are clinically observed to eventually establish a gatekeeper T790M mutation in the ATP-binding site of the EGFR kinase domain, which is primarily responsible for acquired drug resistance to cancers. Over the past decades, a number of noncovalent, wild-type-sparing and ATP-competitive inhibitors (NWAIs) were reported to selectively target the T790M mutant over wild-type kinase, which are independent of the traditional inhibitor classification system that categorizes EGFR TKIs into four generations. Here, we systematically investigated the intermolecular interaction of wild-type EGFR (EGFR${}^{\text{W}\text{T}})$ and its T790M mutant (EGFR${}^{\text{T}790\text{M}})$ with 15 existing NWAI inhibitors, paying attention to the structural and energetic responses of inhibitor ligands to the gatekeeper mutation. It was revealed that the NWAIs can be typed into three classes I, II and III, which can form S$\cdot \cdot \cdot \pi$ interactions, hydrophobic (van der Waals) contacts and weak hydrogen (halogen) bonding with the side-chain thioether moiety of the mutant Met790 residue, respectively, thus conferring additional affinity and specificity to inhibitor ligands upon the T790M mutation. In addition, we further performed 2D-chemical similarity search to identify new class I NWAIs, from which two Staurosporine analogs (i.e. UCN01 and ZHD0501) were identified to have a good selectivity for EGFR${}^{\text{T}790\text{M}}$ over EGFR${}^{\text{W}\text{T}}$. They can be exploited as promising leading chemical scaffolds to further develop potent, selective, wild-type-sparing NWAI inhibitors of EGFR${}^{\text{T}790\text{M}}$ gatekeeper mutant.

Vanillic acid’s ability to effectively quench-free radicals has sparked widespread interest in its antioxidant potential. The title molecule’s structure was optimized using the Gaussian 16 program with the B3LYP/6-31+G($d$,$p)$ basis set. Natural bond orbital (NBO) calculations reveal that the O${}_{(2)}$-H${}_{(19)}$ bond in vanillic acid is labile, facilitating the generation of a free radical. The high-bond dissociation energy (BDE) of vanillic acid raises concerns about its efficacy as an antioxidant, particularly when compared to gallic acid (GA) and butylated hydroxy toluene (BHT). Introduction of electron-donating groups (EDGs) at the 10th position significantly enhanced the antioxidant activity of vanillic acid. Vanillic acid and its derivatives show enhanced safety profiles, outperforming BHT in toxicological studies. This paper presents a systematic investigation of vanillic acid and its derivatives, focusing on structural analysis, solvent effects, antioxidant mechanism and toxicological evaluation.

The spread of dengue fever has resulted in several deaths for which no drug is currently efficacious. A potential target for the development of an antiviral drug that prevents conformational changes and interferes with membrane fusion is the Dengue $\beta$-OG binding pocket. This study aimed to identify potential natural product leads with the propensity to inhibit the envelope protein. Three known inhibitors (DV2419-447, NITD449 and Doxycycline) and 43,465 compounds compiled from naturally derived product libraries comprising AfroDb, NANPDB and TCMID were screened against the envelope protein’s energy-minimized structure as an integrated library. After the molecular docking studies involving 7200 prefiltered compounds and three known inhibitors using AutoDock Vina, 620 top-identified hits were physiochemically and pharmacologically profiled using SwissADME. Compared with reported potent inhibitors, the lead compounds were shown to have better binding affinities greater than −8.6 kcal/mol. Four predicted lead compounds comprising ZINC000014721518, ZINC000005195832, ZINC000014819293 and ZINC000004102396 were identified to interact with Thr48, Leu198 and Gln49, which are critical residues in the inhibition of membrane fusion. All the potential leads were predicted to be antiviral and membrane permeability inhibitors with Pa > 0.300 and Pa > 0.500, respectively. ZINC000014756860, ZINC000014819293 and ZINC000003871358 were predicted to be viral entry inhibitors. Structurally similar compounds have been shown to inhibit Dengue virus (DENV) replication. In-depth molecular dynamics simulations, including MM/PBSA computations, further substantiated the protein–ligand complexes’ stability and favorable binding mechanisms with residues Leu198, Ile270, Thr48 and Phe193. Further experimental evaluation is needed to understand their role in inhibiting DENV viral entry.

Background: Cancer remains a significant global health challenge, with ongoing research focused on identifying effective therapeutic targets. Human agmatinase (AGMAT), a binuclear manganese enzyme, has been associated with cancer progression through its role in polyamine production and its involvement in the NO/MAPK/PI3K signaling pathway in lung tissue. Objective: This study aimed to identify potential inhibitors of AGMAT from a library of FDA-approved drugs using computational methods, intending to find novel therapeutic agents for cancer treatment. Methods: The three-dimensional structure of AGMAT was determined using homology modeling, with Pseudomonas guanidinobutyrase (GbuA) serving as the template due to its 74% sequence similarity to AGMAT. The model was validated using PROCHECK, Verify3D, ProSA and ERRAT software. High-throughput virtual screening was conducted on a chemical library of approximately 7922 FDA-approved drugs to identify potential AGMAT inhibitors. Molecular docking simulations assessed the binding affinities of these drugs. Results: The virtual screening identified ten lead FDA-approved molecules: Nemifitidum, Examorelin, Pralmorelin hydrochloride, Nonathymulin, Ebiratide, Lypressin, Histrelin, Agripressin, Cetrorelix and Ornipressin that exhibited significant binding affinities to AGMAT. Conclusion: The identified lead compounds represent promising candidates for further investigation as potential cancer therapeutics targeting AGMAT. These findings provide a basis for future experimental validation and the development of new drugs toward cancer treatments.

Neurological disorders (NDs) affect 15% of the human population globally, causing cognitive and physical disabilities. There is an increase in cases of NDs with the aging populations that challenges accessible healthcare. NDs, like Parkinson’s, and Alzheimer’s, cause neuronal loss and impairments. Misfolded protein accumulation characterizes disorders like Alzheimer’s and Parkinson’s. Amyloid beta (A$\beta$) has two main variants, A$\beta$${}_{40}$ and A$\beta$${}_{42}$. A$\beta$ accumulation triggers microglia activation, and synaptic loss in Alzheimer’s disease (AD). A$\beta$ induces neuronal dam-age, forming amyloid plaques. Soluble A$\beta$ oligomers are neurotoxic, disrupting neuronal func-tions. Therefore, A$\beta$ aggregation inhibition is a potential therapeutic strategy for AD. Molecu-lar dynamics (MD) simulations offer unique insights, especially for investigating structural changes in peptides like A$\beta$ interacting with inhibitors. Computational methods provide in-sights into the driving forces behind the aggregation of monomeric proteins at early stages. Using computational methods, this study explores how coumarin inhibits A$\beta$ oligomerization and aggregation, revealing reduced $\beta$-sheet formation and potential drug development in-sights. Coumarin interacted at the high aggregation propensity and hydrophobic region of A$\beta$ and stabilized it. When 10 molecules A$\beta$${}_{16-21}$ were simulated, $\beta$-sheet content stood at 2.27% within the initial 5 ns, progressively reaching 11.35% until 50 ns. This upward trend continued, reaching an average $\beta$-sheet content as 22.83% for entire simulation. However, the introduc-tion of 250 mM coumarin during the simulation diminished the formation of $\beta$-sheets to 10.59%. Overall, our studies suggest that coumarin could serve as a potential preventive and therapeutic agent for inhibiting A$\beta$ oligomerization and aggregation.

Penicillin resistance is a commonly present and controversial matter due to the misuse by people for various reasons. However, few studies have examined the bioactivity of 5- and 6- membered rings. In this study, we aimed to synthesize a new compound containing a 5-membered ring following a short and low-cost method and combined it with oxazepine ring via Schiff bases to produce a bicyclic molecule (Lactozepine). In vitro examinations were conducted to assess the bioactivity of the prepared compound, including anti-bacterial, anti-fungal and antioxidant activities, which showed a wide zone of inhibition of lactozepine against Streptococcus pneumoniae but no inhibition was shown against Klebsiella pneumoniae and Staphylococcus aureus except at a high concentration similar to the result of the anti-fungal assessment. Furthermore, lactozepine showed significant antioxidant activity against free radical formation. The molecular modeling and docking assessment showed the ability of lactozepine to bind to bacterial proteins and inhibit their growth with the lowest free energy for the greatest and strongest binding affinity with the PDB crystal structures 1VQQ, 2WAE, 1PYY and 1IYS ranging from −6.5 and −7.9 kcal/mol. Moreover, the molecular dynamics (MD) simulation showed that RMSF for the assessed protein’s amino acids remained consistent and tightly bound to lactozepine in the dynamic state. The novel compound lactozepine, with $\delta$-lactam rings attached to oxazepine showed bioactivity promising for in vivo studies in the future.

Background: Aging is a complex biological process and is characterized by a gradual decline in physiological functions and increased vulnerability to various diseases. It is linked with the genes known as Monocyte Chemoattractant Protein-1 (MCP-1) and Vascular Endothelial Growth Factor (VEGF). MCP-1 is a key protein in generating immune response and VEGF is involved in angiogenesis. Objectives: This is a cross-sectional experimental study that aims to observe interplay between MCP-1 SNP (rs1024611) and VEGF SNP (rs699947) with aging and lifestyle habits. It delves into the biological pathways implicated in aging, as well as the impact of lifestyle elements such as dietary habits, tobacco use and physical activity on MCP-1 and VEGF expression levels. Method: The study involved the selection of 60 samples from elderly individuals and 60 samples from healthy individuals as control. The selection process was done by filling the proforma having questions related to the lifestyle habits and the use of medication since they can interfere with gene functioning. After that DNA extraction, and the identification of gene presence through PCR analysis. The assessment of PCR outcomes revealed a prevalence of the CC allele in both the experimental and control cohorts for both MCP-1 and VEGF, highlighting the critical role of these genes in the aging process. Furthermore, it posits that variations in the VEGF gene may hold significant sway over aging. Bioinformatics techniques were used to explore the relationship between MCP-1 and VEGF, employing Cytoscape STRING, KEGG pathway analysis and GO enrichment to analyze the interactions between these two genes. Results: It was observed that these genes are interconnected, functioning under the influence of the Tp65 transcriptional factor. The research findings also put forth the notion that dietary habits and physical exercise could potentially modulate the expression of these genes, thereby influencing the process of healthy aging. Those who adopted healthy lifestyle showed CC and TT genotypes for MCP-1 and VEGF respectively therefore, showing slow and healthy aging. Conclusions: The conclusion of this article suggests that the MCP-1 and VEGF genes play a crucial role in immune response, inflammation and aging. The study highlights the potential interaction between these genes in monocyte recruitment and angiogenesis.

Background: Monoamine oxidase-B (MAO-B) is crucial in breaking down biogenic and dietary amines, with its dysregulation linked to Parkinson’s disease. Objective: This study aims to explore the MAO-B inhibitory potential of 34 hydrazine-linked thiazole derivatives through computational techniques. Methods: Molecular docking against MAO-B (2BYB) assessed binding affinity, complemented by MMGBSA for binding energy evaluation. Pharmacophore modeling and QSAR analysis identified structural features essential for inhibition, while molecular dynamics (MD) simulations validated the stability of ligand-MAO-B complexes. Results: Compound T18 exhibited outstanding binding affinity, while T9 showed the lowest. In vitro studies revealed that T2 had the weakest inhibitory potential, while T19 demonstrated the highest. Pharmacophore modeling identified the six-feature hypothesis ADHRRR_1 as the key structural feature for optimal inhibition. QSAR analysis provided insight into the importance of pharmacophoric features, including the electron-deficient 3-pyridine at N1 of hydrazine, which acts as an electron-withdrawing group that enhances interactions with the enzyme active site, making pyridine a valuable pharmacophore. Additionally, the electronegative fluorinated phenyl ring at C4 of thiazole enhances blood-brain barrier (BBB) permeability and selectivity for MAO-B. Notably, the methyl group on T19 acted as a hydrophobic feature, increasing electron density and boosting inhibitory activity. MD simulations confirmed the stability of the T18/2BYB and T19/2BYB complexes. Furthermore, T19 displayed superior CNS activity and BBB permeability, confirming the methyl group as crucial for enhanced action. Conclusion: These findings underscore the potential of hydrazine-linked thiazole derivatives as potent MAO-B inhibitors. Future in vivo studies are essential to explore their therapeutic benefits further.

ABSTRACT: Tyrosinase and tyrosinase-related protein-2 (Tyrp2) play a pivotal role in melanin production within melanocytes. Both share a high degree of structural and sequence similarity, with a Root-Mean-Square Deviation (RMSD) of 0.75 Å and 62% sequence similarity, including 43% sequence identity. Despite these similarities, differences in the allosteric sites, particularly the residues that constitute these sites, contribute to distinct regulatory mechanisms. This study elucidates the contrasting allosteric modulation of tyrosinase and Tyrp2 by two flavonoids: (a) luteolin and (b) apigenin, respectively. Luteolin demonstrated its allosteric inhibitory property against tyrosinase by disturbing the spatial arrangement of histidine residues critical for copper coordination, essential for enzymatic activity. Conversely, apigenin serves as an allosteric activator for Tyrp2, enhancing structural stability and maintaining the active site conformation. Despite the structural resemblance between luteolin and apigenin, differentiated by a single hydroxyl group, their impact on melanin synthesis diverges — luteolin inhibits, whereas apigenin stimulates the process. Both showed high binding affinity at the allosteric site of tyrosinase and Tyrp2. Luteolin significantly alters the spatial arrangement of key histidine residues (HIS180, HIS202 and HIS211), forming coordination bonds in tyrosinase, affecting copper coordination and coordination with the peroxide (O₂2⁻) ion. However, apigenin did not remain bound to tyrosinase for an extended period, ruling out its role as an allosteric modulator. In contrast, apigenin stayed at the allosteric site of the Tyrp2 protein and showed a positive allosteric regulator role. The findings offer a mechanistic view of melanin synthesis regulation, demonstrating the potential of subtle structural variations in modulators to selectively influence enzyme activity in related biosynthetic pathways. This underscores the intricate control within melanogenic systems and the possibility of targeting these pathways for therapeutic and cosmetic applications.

We report the molecular engineering of new small molecule-based medium band gap nonfullerene acceptors containing a strong electron acceptor backbone of DPP attached to the $\pi$-spacer-based furan linker. We systematically designed five new designed molecules (H1−H5) and studied their structural, optical, photovoltaic and optoelectronic characteristics. We employed advanced quantum chemical approaches to characterize these molecules (H1–H5) and synthetic reference molecule R. The designed molecules exhibit improved light absorption and narrower energy bandgaps in contrast to R. Moreover, a lower excitation energy of these molecules (H1−H5) enables easier excitation and phase separation in the excited states. Analysis of the geometric and physiochemical properties provides evidence of the enhanced photovoltaic and optoelectronic characteristics of these molecules in comparison to the R molecule and other molecules with similar structures that have been previously reported. Among all these designed series, H3 stands out with a minimal 1.99 eV band gap, excellent hole (${\lambda }_h$ 0.0079 eV) and electron (${\lambda }_e$ 0.0076 eV) mobility, low binding energy ($E_b$ 0.42 eV) and highly red-shifted absorption characteristics. Furthermore, these molecules also displayed good electron and hole mobilities, indicating their tremendous potential in producing high-efficiency organic solar cells. Therefore, this study showcases the molecular modeling and effectiveness of these DPP and furan-containing molecules and their promising potential for organic photovoltaics.

The reaction of $p$-methylbenzaldehyde and 5,5-dimethyl-1,3-cyclohexanedione with the addition of HCl yielded 3,3,6,6-tetramethyl-9-($p$-tolyl)-3,4,5,6,7,9-hexahydro-1$H$-xanthene-1,8(2$H)$-dione (TTHD). X-ray diffraction method was used for verification of the crystal structure. Supramolecular assembly was studied via various intermolecular interactions and explored via Hirshfeld surface analysis. The contact-making ability of the pairs of atoms is determined by enrichment ratios. The stability of the present compound is determined through interaction energies. Electronic structure calculations are conducted at the wb97xd/def2tzvp theoretical level. Charge transfer and reactivity are estimated through natural bonding orbital (NBO) charge analysis. Global reactivity parameters are calculated and compared with the reported molecule. Quantum theory of atoms in molecules (QTAIM) is exploited to unveil the bonding’s nature and van der Waals interactions (vdW). Electron localizing function (ELF), and localized orbital locator (LOL) are also employed to investigate electronic properties. The optical and nonlinear optical (NLO) properties of the present compound are examined using the density functional theory (DFT) method.

A series of novel hybrid bipyrimidine derivatives were designed, synthesized and evaluated for their anticancer activity against the breast cancer cell line MCF-7 and the lung cancer cell line A549. The structures of all the synthesized molecules were confirmed using various spectroscopic techniques. Molecular docking studies were conducted using Maestro software from Schrödinger, targeting the crystal structure of the ErbB4 kinase (PDB ID: 3BBT). Lapatinib and gefitinib were used as reference drugs to compare binding affinities with the ErbB family of receptor tyrosine kinases. Several of the synthesized bipyrimidine derivatives demonstrated promising activity, with IC${}_{50}$ values comparable to the standard drug doxorubicin and gefitinib. Notably, compound PP-10 exhibited equipotent effects when compared to the reference drugs in both breast and lung cancer cell lines. Additionally, compounds PP-07 and PP-09 showed significant potency against the MCF-7 cell line, while compounds PP-02, PP-09, PP-11 and PP-14 were active against the A549 cell line. These novel hybrid bipyrimidine derivatives served as potential lead molecules in the development of novel drug-like molecules for the treatment of breast and lung cancer.

Rhododendron arboreum Sm. (Burans) (family Ericaceae) has traditionally been used in Indian medicine to treat liver disorders. However, its mechanism against non-alcoholic fatty liver disease (NAFLD) remains elusive. This study utilized in silico methods – network pharmacology, ADMET prediction, molecular docking and molecular dynamics (MD) simulations for mechanistic exploration of Rhododendron arboreum leaves (RAL) in NAFLD. Bioactive compounds were sourced from open databases and assessed for drug-likeness and ADMET profiles. Network pharmacology identified key protein interactions using the STRING platform. GO analysis identified galactose metabolism, pentose and glucuronate interconversions and other processes in treating NAFLD. Molecular docking revealed that amyrin and pectolinarigenin had the highest binding affinities, with dock scores of –12.2 kcal/mol (AKR1C3-amyrin), –10.2 kcal/mol (PI3K-amyrin), –9.3 kcal/mol (AKR1C3-pectolinarigenin) and –9.6 kcal/mol (HSD17B1-pectolinarigenin). MD simulations, focusing on RMSD and RMSF analyses, confirmed the stability of these interactions. The RMSD graphs revealed stable binding pocket regions, highlighted in pink. Notably, the RMSF values for PHE (B:306) in the AKR1C3-amyrin complex and ARG (A:294) in the PI3K-amyrin interaction were 0.623 nm and 0.1586 nm, respectively, indicating stable ligand interactions. Our findings holistically clarify toxicity data, potential bioactives targets and molecular mechanisms of RAL against NAFLD, paving the way for future research.

Aims: This study aims to prepare and investigate the potential of theobromine derivative-loaded chitosomes as an effective anticancer drug. Background: $N$-Benzyl-2-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1$H$-purin-1-yl)acetamide (T-1-BA) exhibited promising anticancer potential. Loaded chitosomes, highlighting their suitability as a drug delivery system. The study builds on the significance of targeted drug delivery systems for enhanced anticancer efficacy. Objectives: To prepare T-1-BA-loaded chitosomes (T-1-BA-PC-CS complex) using the thin film hydration technique. To examine the colloidal characteristics, entrapment efficiency, and stability of the T-1-BA-PC-CS complex. To assess the in vitro anticancer efficacy of the T-1-BA-PC-CS complex against Hct116 and A549 cancer cell lines comparing the free T-1-BA, blank chitosomes, and the standard EGFR inhibitor, Lapatinib. Methods: The T-1-BA-PC-CS complex was prepared through the thin film hydration technique. Colloidal characteristics, including particle size, PDI, and zeta potential, were examined. In vitro anticancer efficacy was assessed through IC${}_{50}$ values, comparative analyses, SI calculations, cell cycle analysis, flow cytometry, and wound healing assays. Results: The T-1-BA-PC-CS complex demonstrated reduced IC${}_{50}$ values against Hct116 and A549 cell lines, indicating enhanced cytotoxicity compared to free T-1-BA and blank chitosomes. Comparative analyses highlighted superior anticancer activity. SI values indicated preferential cytotoxic effects on cancer cell lines. Flow cytometry analysis revealed cell cycle alterations and increased apoptosis. Wound healing assays showed a significant impact on migration and wound healing in A549 cells. Conclusion: The findings suggest that the T-1-BA-PC-CS complex holds great promise as an anticancer therapeutic by efficiently inducing favorable alterations in cell cycle phases and apoptosis, demonstrating its potential for further development in cancer treatment.

Here, we provide the synthesis process as well as theoretical and experimental research on the molecule known as 7-hydroxy-2-(3,4-dihydroxyphenyl)-3-(piperidin-4-yloxy)-4H-chromen-4-one (7THFP). Quantum mechanical calculations (QM) using several functional levels at a standard basis set have been used to calculate all QM calculations and molecular descriptors. Computational techniques were used to obtain the whole range of vibrational frequencies, IR intensity and Raman activity, all showing excellent agreement with the observed results. The molecule’s electron transport characteristics were explained by Mulliken, NBO, mapped isosurface electron density and Highest Occupied Molecular Orbitals (HOMO)-Lowest Unoccupied Molecular Orbitals (LUMO) investigations. The energy difference between the molecular orbitals (MOs) has also been anticipated. The drug candidate’s ADMET and Lipinski’s rule of five models were used to predict its physicochemical and pharmacokinetic properties, including bioactivity score, lipophilicity and toxicity profiles. The physicochemical profiles of 7THFP indicate favorable drug-likeness, bioactivity and reduced toxicity. Subsequently, molecular docking (MD) analyses were conducted to forecast the ligand’s inhibitory impact on the enzymes. The docking score estimation and in vitro analysis of the drug compound validate its anticancer activity. Lastly, the title molecule was evaluated for its proliferation and cytotoxicity effects on human MCF-7 cell lines. These investigations demonstrate that the product exhibits promising characteristics as a drug candidate and may serve as a model for further enhancement.