Journal of Computational Biophysics and Chemistry

Amberboa ramosa Roxb. (Asteraceae), commonly known as “Badaward”, has been used for the treatment of tumors from ancient times. In this study, we aimed to scientifically authenticate the use of A. ramosa for breast cancer treatment. The whole plant fractions of A. ramosa were evaluated for their cytotoxic properties against MDA-MB-231 breast cancer cell lines. Among these fractions, Pet. ether, ethyl acetate, and ethanolic fractions exhibited considerable levels of cytotoxicity against MDA-MB-231 cells with ${\text{IC}}_{50}$ values of 78.55, 90.60, and 92.92 $\mu$g/mL, respectively. The cell migration significantly decreased in ethyl acetate and ethanolic fractions. GC–MS was used to analyze the phytochemical profile of bioactive fractions, which revealed the presence of long-chain hydrocarbons, carboxylic acids, esters, alcohols, and terpenoids. Subsequently, the 96 compounds present in bioactive fractions were efficiently docked with EGFR and microtubule protein to evaluate affinity towards the targets. Eight common compounds were achieved using a docking-based approach against both target proteins, which showed similar interaction patterns as the reference inhibitors (colchicine and erlotinib). The key interactions revealed the potential of screened compounds as promising hits. 2-[1,2-Dihydroxyethyl]-9-[$\alpha$-d-ribofuranosyl]hypoxanthine showed the best dock score of −9.337 and −8.548 kcal/mol against EGFR and microtubule, respectively. 5-Oxo-cystofuranoquinol exhibited better dock score as well as binding energy against both targets. Chemical features present in the 08 dual inhibitors were also matched from the present EGFR and microtubule inhibitors for comparing the anticancer potential. Thus, this research revealed many new directions for developing natural lead compounds from Amberboa ramosa as dual inhibitors for treating breast cancer.

This study investigates the impact of six novel (SPZ1–SPZ6) small molecular conjugated nonfullerene acceptors (NFAs), for organic solar cells (OSCs). The designed NFAs are characterized by various advanced quantum chemical simulations of density functional theory (DFT) and time-dependent (TD-DFT) approaches. We revealed in-depth information regarding molecules’ structural-property relationship charge transfer and optical absorption characteristics of designed molecules and compared them with synthetic reference molecules (R). The designed SPZ1–SPZ6 molecules exhibit red-shifted absorption, reduced bandgaps and increased extinction coefficients, indicating improved molecular phase separation during thin-film deposition during device fabrication. Moreover, the modeled SPZ1–SPZ6 molecules significantly enhance photophysical, optoelectronic and photovoltaic parameters compared to R. Among these, the designed small molecule SPZ2 exhibits superior UV–Vis absorption of 730.44 nm, surpassing R and others. SPZ2 features the smallest bandgap (2.00 eV) and has a substantial improvement over R’s 2.37 eV, and this is due to our efficient molecular modeling strategy. Further investigation revealed efficient charge transfer between the SPZ2 acceptor molecule and PTB7-Th donor molecule complex, making this design capable of producing efficient OSCs in the future.

The fibroblast growth factor receptor 2 (FGFR2), a transmembrane receptor tyrosine kinase, is implicated in a plethora of human cancers, including intrahepatic cholangiocarcinomas. The clinically relevant V564F gatekeeper mutation conferred resistance to the current FGFR2 drug−Pemigatinib. Here, we conducted integrated computational methods to compare the protein−ligand interactions between the FGFR2 kinase domain in the wild-type and V564F mutant states and Pemigatinib. Based on molecular docking, molecular dynamic simulations and hydrogen bond analysis, we revealed that the reduced hydrogen bonding interactions in the V564F mutant were the key factor to decrease the binding affinity of Pemigatinib to the FGFR2. The per-residue free energy decomposition analysis implemented by the molecular mechanics/generalized born surface area method revealed the reduced contributions from the key residues G488, F564 and A567 located at the kinase hinge domain were responsible for the decreased binding affinity in the V564F mutant. This study elucidated the molecular mechanism for the resistance of Pemigatinib in FGFR2 triggered by the V564F mutation and may provide insights for future drug development and optimization.

Diabetes, a chronic metabolic disease, has become a severe health problem worldwide. According to the latest data from the International Diabetes Federation (IDF), there were 537 million diabetic mellitus (DM) patients worldwide in 2021, expected to increase to 783 million by 2045. Over 90% of people with diabetes have type 2 diabetes, which is driven by socio-economic, demographic, environmental, and genetic factors. Diabetes is still a major global health issue, with prevalence rates rising all across the world. This not only imposes a significant burden on healthcare systems but also impacts the quality of life of affected individuals and their families. Therefore, there is a continuous high demand worldwide to develop novel, more effective, and easily affordable medications against diabetes. This paper illustrates the in-vitro antidiabetic activity and probable binding mechanism prediction of phytoconstituents of Allamanda cathartica against type 2 diabetes molecular targets. Through the application of bioactivity score prediction, molecular docking, and ADMET prediction approach, the potential and selective phytoconstituents with the highest binding affinity and lower toxicity were gained from the curated datasets. Further molecular dynamics simulations and DFT calculations were carried out to identify the favorable binding conformations when the top-scored phytoconstituents bind with the PPAR$\gamma$ receptors compared to the rosiglitazone. Compound AC2 interacts with the PPAR$\gamma$ proteins by forming seven hydrogen bonds with the amino acid residues Phe282, His449, Tyr327, His323, and Ser289. The ligand was bound to the protein during the simulation since none of the complex conformations was unstable, and no unfolding or folding occurred. Our results provided an approach to further design and optimize the natural product-inspired small druglike molecules as potential antidiabetic agents. This study highlighted that the phytoconstituents of Allamanda cathartica have antidiabetic potential through the binding of PPAR$\gamma$, $\alpha$-amylase and $\alpha$-glucosidase proteins that can be further explored for novel antidiabetic drug development.

The $\alpha$7 nicotinic acetylcholine receptor (nAChR) is a neurotransmitter receptor and a promising therapeutic target for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In this study, we used deep learning-based classification modeling, molecular docking, and intracellular calcium signal detection experiments to identify positive allosteric modulators (PAMs) of the $\alpha$7 nAChR from natural tobacco products. First, we used a classification prediction model based on the direct message-passing neural network (D-MPNN) and molecular docking to predict potential $\alpha$7 PAMs. Subsequently, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed to determine its pharmacological properties and minimal toxic side effects, leading to the selection of three natural compounds for in vitro activity validation. Calcium signaling assay experiments revealed that diosmetin can enhance nicotine-induced calcium ion signaling. 100 ns molecular dynamics (MD) simulations indicated that diosmetin can form a dense and stable complex with $\alpha$7 nAChR. This study provides valuable insights for the design of more effective and selective ligands for the $\alpha$7 nAChR.

A new series of benzenesulfonamide derivatives, namely N-(1-(2-chloropyrimidin-4-yl)-1$H$-indazol-5-yl) compounds (4a-i) and N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1$H$-indazol-5-yl) derivatives (5a-i), were synthesized. This was achieved by reducing 1-(2-halopyrimidin-4-yl)-5-nitro-1$H$-indazole (3) with SnCl₂, followed by reacting with various aryl sulphonyl chlorides in pyridine. Structural confirmation was carried out through IR, 1H-NMR, ${}^{13}$C-NMR and mass spectral methods. Anticancer activity evaluation of compounds 4a-i and 5a-i revealed that N-(1-(2-chloropyrimidin-4-yl)-6-ethoxy-1H-indazol-5-yl)-2-nitrobenzenesulfonamide (5b) displayed exceptional efficacy. Molecular dynamics simulations were employed to rigorously assess the stability of ligand–protein complexes, highlighting a consistent and robust binding of the most potent compound within the binding sites of target proteins. The results unequivocally affirmed the remarkable anticancer activity, supported by comprehensive molecular docking analyses uncovering intricate interactions involving hydrogen bonds, electrostatic forces and hydrophobic contacts. These findings collectively offer invaluable insights into the complex molecular structure and dynamics of receptor target sites, establishing a robust foundation for the development of novel and potent anticancer agents with promising pharmaceutical implications.

The application of fungicides for commercial purposes has grown in response to increased food demand and shifting disease patterns. However, there is a scarcity of studies demonstrating their proper degradation. Due to the expanding global population, there is a heightened need for more agriculture to fulfill the growing demand for food, and this necessitates safeguarding crops from pests and diseases. Disease outbreaks in crops can result in the loss of food and the depletion of valuable resources. According to the European Union, organic fungicides constitute 60% of all fungicide sales, while synthetic fungicides make up the remaining 40% of pesticide sales. Fungicide usage is indispensable but needs to be considered within the context of potential environmental risks. Nonetheless, there is a pressing need to break down fungicides to preserve the natural environment. Our research is centered on hybrid enzymes derived from S. marcescens, which exhibit the capability to degrade fungicides. We employed computational techniques to assess the enzymes’ effectiveness in breaking down fungicides. S. marcescens was isolated from soil and identified through 16s rRNA analysis. Chitanase and lipase, enzymes identified in S. marcescens, can individually break down fungicides, as confirmed by auto-dock vina docking simulations. Notably, the combined action of these two enzymes surpasses the performance of individual docking, a result also corroborated by auto-dock vina. To further establish the efficacy and degradability of this approach, computational techniques were employed. In the future, it may be possible to create an in vitro antifungal agent, which could be categorized as a bioactive agent.

Protein kinase C isoform $\iota$ (PKC$\iota )$ is an essential regulator of diverse neurobiological signaling pathways, which has been implicated in general anesthetic action and a variety of nervous neoplasms. Traditional efforts have been primarily addressed on the development of small-molecule inhibitors to target the catalytic or regulatory domain of this kinase. Instead, we herein reported a rational chemical modification of Par3 pseudosubstrate peptide to target the kinase domain with improved affinity and specificity. Structural and energetic analysis suggested that the Par3 peptide can be divided into two binding-independent sections; they are separately anchored to the substrate-binding pocket of PKC$\iota$ with two aromatic anchor residues Phe818 and Phe823. The side-chain phenyl group of these two aromatic residues was systematically substituted by different halogen moieties at $o$-, $m$- and $p$-positions of the phenyl group. It is revealed that the $p$-bromination of Par3 Phe818 and the $p$-iodinization of Par3 Phe823 residue can separately form two geometrically and energetically satisfactory orthogonal halogen (X)-bond/hydrogen (H)-bond [ortX/H] motifs across Par3 complex interface with PKC$\iota$; they co-define a so-called ortX/H system and were demonstrated to improve both the binding affinity and recognition specificity of the kinase–peptide interaction by integrating in silico analysis and in vitro assay. The peptide affinity promotes 23.5-fold and 6.6-fold upon the formation of ortX/H motif-I and motif-II, respectively, which further increases to 43.5-fold by forming the complete ortX/H system, indicating cooperativity between the two motifs in the system. In addition, we also demonstrated that the ortX/H system can considerably enhance the peptide selectivity for its cognate PKC$\iota$ and noncogante isoforms PKC$\alpha$ and PKC$\delta$.