Journal of Computational Biophysics and Chemistry

Xanthine dehydrogenase (XDH) contributes significantly to generating reactive oxygen species in coronary artery disease (CAD). XDH has been proposed as a therapeutic target, but its genetic variants could affect protein structure and drug response. We aimed to assess protein structure modification occur due to genetic variants and to screen 215 CAD drugs for their utility in personalized CAD treatment against the XDH variants. A series of computational methods were implemented to identify pathogenic variants that cause XDH structure instability localized at the con served regions contributing to functional significance. Then, the XDH structures with the pathogenic variants were modeled using two different approaches to select the best models for docking with the CAD drugs. Finally, the stability of the docked complexes and their ability to transfer electrons were evaluated using molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculation. Among 751 variants examined; R149C and Q919R showed high pathogenicity, localized in conserved regions could alter protein structure and function. Further, docking of CAD drugs against XDH (native, R149C and Q919R) showed vericiguat with higher affinity, ranging from −7.95 kcal/mol to −10.41 kcal/mol, than the well-known XDH inhibitor (febuxostat, −5.73 kcal/mol to −8.35 kcal/mol). This indicates that vericiguat will be effective in CAD treatment, regardless of the XDH variants. Additionally, MD simulation and QM/MM confirmed vericiguat stability and electron transfer ability to form hydrogen bonds with the XDH protein. In conclusion, vericiguat will be beneficial for the personalized treatment of CAD by inhibiting XDH variants. Additional clinical studies are necessary to confirm our findings.

A DNA tumor virus called Epstein-Barr virus (EBV) is the cause of 1-2% of human cancers. EBV-associated carcinogenesis is caused by a persistent latent infection. The shortage of antiviral medications or vaccinations to control the virus led to a significant percentage of critically sickness individuals needing to be hospitalized. In the absence of an effective vaccine and approved drug, there is an immediate need for treatments that can combat EBV infection. Epstein Barr nuclear antigen 1 (EBNA1) is continually expressed in all malignancies linked to EBV; it is a desirable target for curative interference. Herein, natural product compounds from the Nuclei of Bioassays, Ecophysiology and Biosynthesis of Natural Products (NuBBE) database were mined to identify potent EBNA1 inhibitors. The performance of the molecular docking technique was initially assessed in expecting the ligand-target binding pose according to the available experimental data. On the basis of the estimated docking protocol, the NuBBE database was virtually screened toward the EBNA1 protein, and the natural compounds with binding scores less than KWG (calc. $-7.8$ kcal/mol) were subjected to molecular dynamics (MD) simulations followed by binding energy ($\mathrm{\Delta }{G}_{\text{binding}}$) calculation using MM/GBSA approach. Based on binding energy computations, NuBBE1460 revealed superior $\mathrm{\Delta }{G}_{\text{binding}}$ with a value of $-36.2$ kcal/mol, compared to KWG (calc. $-32.4$ kcal/mol). Post-MD analyses displayed a high steadiness of NuBBE1460 within the EBNA1 protein binding pocket. Furthermore, the physicochemical, pharmacokinetic and toxicity features of the identified compound were predicted, demonstrating high degrees of its oral bioavailability. The energetical and geometrical properties of NuBBE1460 were calculated using the DFT method. Conclusively, this study offers NuBBE1460 obtained from natural sources as a lead EBNA1 inhibitor for future investigation and development as a therapeutic for EBV.

Anti-microbial resistance has emerged as the leading cause of death worldwide with the rise of multidrug-resistant (MDR) bacteria, the need for novel anti-microbials to treat serious illnesses has become a great necessity. Hence, in this study, we aimed to design and synthesize benzothiazole-coupled azetidinone derivatives (GD1-GD12) as novel antibacterial agents. The synthesized compounds were elucidated by nuclear magnetic resonance, infrared and mass spectroscopy. The antibacterial activities of these compounds were tested against antibiotic-susceptible and MDR strains of bacteria. In addition, we performed ADME profiling, molecular docking and molecular dynamic simulations, principle component analysis, dynamic cross-correlation map and free-energy landscape to assess the binding of synthesized compounds with the $\beta$-lactamase. Among the synthesized compounds GD6 and GD5 displayed minimum inhibitory concentrations of 12.5 $\mu$g/mL and 50 $\mu$g/mL against MDR strains of E. coli; more effective than standard. The molecular docking of designed molecules was performed against $\mu$-lactamase enzyme and the stability of the complex was vali-dated. The pharmacokinetic profile displayed the compounds to possess druggable properties within the suitable ranges. The in silico approach displayed compound GD6 to be stable with $\beta$-lactamase enzyme; indicating the mechanism for these compounds to be via inhibition of $\beta$-lactamase. The novel anti-microbial compounds assessed against susceptible and MDR strains of bacteria possess antibacterial potential via the inhibition of $\beta$-lactamase. The aforementioned data will be crucial to the development of novel broad-spectrum antibacterial compounds.

Osteoblasts originate from mesenchymal stem cells (MSCs) and their maturation is regulated by numerous genes. However, specific genes that play decisive roles in osteoblast maturation are not completely understood. Herein, we propose a new algorithm called SGCAL to identify sensitive gene combinations during osteoblast development and decode the regulatory roles of sensitive gene combinations in cell development. In contrast to conventional gene identification algorithms, the SGCAL algorithm, which is based on a combination of ARNN-LNE iterative cycles, quantitatively evaluates the sensitivity of genes by analyzing the average network entropy before and after gene perturbation. We verified that osteoblast development is fundamentally regulated by an overall sensitive network formed by specific genes. Moreover, we explored the roles of these sensitive genes and their combinations in the transition time point of the initial state of network change. Our algorithm was validated on two independent mouse osteoblast development datasets, successfully identifying sensitive genes and their combinations in both datasets and revealing that gene combinations containing Col1a1 can exhibit significant sensitivity. This study demonstrated the universality of cell fate and network regulation, offering new insights and a theoretical basis for the treatment and repair of bone diseases

A wide range of bioactive compounds have been created using the versatile pharmacophore pyrimidine. In order to improve biological applications, we, therefore, envisioned adding these privileged moieties. In this work, we developed an efficient 2-aminopyrimidine derivatives. We further investigated the anticancer activity of all the compounds against colon cancer cell lines COLO-205 and HT-29. Out of several compounds synthesized, two compounds SD2 and SD4 have shown comparable potent anticancer activity when compared to standard Cabozantinib. The most potent cytotoxic compound against colon cancer cells in our study was found to be SD2 with an IC50 value of 9.57 $\mu$M. The investigation from molecular docking showed the best binding affinity. The complex stability within an enzyme’s pocket was demonstrated by the molecular dynamic simulation running for 100 ns.

Tuberculosis (TB) remains a global health concern, necessitating the continuous search for novel therapeutic agents to combat drug-resistant strains and enhance treatment efficacy. The present study focuses on designing, synthesizing, and exploring quinoline analogues as potential anti-tubercular agents. Quinoline scaffolds like bedaquiline inhibit the ATP synthase enzyme involved in energy production. A diverse library of 19 quinoline derivatives was sys tematically synthesized through rational structural modifications. The quinoline analogues were evaluated for their anti-tubercular activity against Mycobacterium tuberculosis (M.tb). Furthermore, the study delves into the molecular interactions between the synthesized quinoline derivatives and M.tb ATP synthase, shedding light on the underlying mechanisms of their anti-tubercular activity. The initial in-vitro screening revealed that some of the designed molecules were active against M.tb, making them potential candidates for further development.

This study explores the repurposing of Food and Drug Administration (FDA)-approved drugs as potential inhibitors of SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication. Initially, 3009 FDA approved drugs were screened to identify candidates structurally similar to the co-crystallized ligand XT7 in the SARS-CoV-2 PLpro complex (PDB ID: 7LBR). A fingerprint analysis narrowed the selection to the top 5% )150 drugs) most structurally akin to XT7, followed by a more refined structural similarity test that identified the top 1% (30 drugs). Molecular docking studies highlighted several compounds with strong binding affinities to the SARS-CoV-2 PLpro. Notably, Fedratinib exhibited a particularly robust binding energy of $-20.54$kcal/mol and was chosen for further investigation. Subsequent molecular dynamics (MD) simulations over 100 ns confirmed the stability and efficacy of Fedratinib’s binding, as evidenced by favorable energetic and dynamic profiles. The molecular mechanics-generalized born surface area (MM-GBSA) calculations corroborated these findings, revealing a binding energy of $-24.36$kcal/mol. Additionally, PLIP, ProLIF, and PCAT analyses further validated the stability and interactions of the PLpro-Fedratinib complex observed during the MD simulations. Overall, our results indicate that Fedratinib, an FDA-approved drug, demonstrates promising potential as an inhibitor of SARS-CoV-2 PLpro, warranting further in vitro and in vivo experimental validation as well as potential clinical evaluation.

The activation of the Neuraminidase 3 (NEU3) enzyme has been associated with the hyperphosphoryla-tion of Epidermal Growth Factor Receptor (EGFR) in Nonsmall Cell Lung Carcinoma (NSCLC). Existing EGFR inhibitors (such as gefitinib, erlotinib, lapatinib, icotinib, afatinib and osimertinib) reduce the hyperactivation of downstream signaling pathways (Akt, Mapk, Jak-Stat, Plc) but fail to completely abolish EGFR hyperphosphorylation. Therefore, co-targeting NEU3 and EGFR presents a greater potential to be used as a combinatorial therapy for NSCLC. This study employs structure guided approaches to elucidate the binding hypothesis of NEU3 and EGFR inhibitors. Toward this, important 3D features associated with high inhibitory potency of NEU3, and EGFR modulators were identified through SAR. The triazole substitution in acetamide dihydropyran carboxylic acid derivatives is mainly responsible for improved inhibitory potency against NEU3. Therefore, the hydrophobic ($\varphi$-H) interaction with the benzene ring and hydrogen bonding with the hydroxyl group of triazole are critical for designing new NEU3 modulators. Molecular Dynamics (MD) simulation studies demonstrate the stability of hydrogen bonding interactions of highly active NEU3 inhibitors with Pro66, Gly199 and Glu410 residues. Similarly, pyrimidine ring of EGFR inhibitors forms stable hydrogen bonds with Lys721 and Asp831 residues, contributing to their inhibitory potency. Our findings suggest that incorporating these identified 3D features associated with triazole and pyrimidine substitutions into a suitable scaffold could be a valuable strategy for developing a new generation of NEU3 and EGFR modulators. This approach offers a potential multi-targeted therapy for NSCLC patients.