Identification of anti-filarial leads against aspartate semialdehyde dehydrogenase of Wolbachia endosymbiont of Brugia malayi: combined molecular docking and molecular dynamics approaches

This study aimed to screen putative drug targets associated with biofilm formation of multidrug-resistant Acinetobacter baumannii and Pseudomonas areugenosa and prioritize carbon nano-fullerene as potential lead molecule by structure-based virtual screening. Based on the functional role, 36 and 83 genes that are involved in biofilm formation of A. baumannii and P. areugenosa respectively were selected and metabolic network was computationally constructed. The genes that lack three-dimensional structures were predicted and validated. Carbon nano-fullerene selected as lead molecule and their drug-likeliness and pharmacokinetics properties were computationally predicted. The binding potential of carbon nano-fullerene toward selected drug targets was modeled and compared with the binding of conventional drugs, doripenem, and polymyxin-B with their usual targets. The stabilities of four best-docked complexes were confirmed by molecular dynamic (MD) simulation. This study suggested that selected genes demonstrated relevant interactions in the constructed metabolic pathways. Carbon fullerene exhibited significant binding abilities to most of the prioritized targets in comparison with the binding of last-resort antibiotics and their usual target. The four best ligand–receptor interactions predicted by molecular docking revealed that stability throughout MD simulation. Notably, carbon fullerene exhibited profound binding with outer membrane protein (OmpA) and ribonuclease-HII (rnhB) of A. baumannii and 2-heptyl-4(1H)-quinolone synthase (pqsBC) and chemotaxis protein (wspA) of P. aeruginosa. Thus, the current study suggested that carbon fullerene was probably used as potential lead molecules toward selected targets of A. baumannii and P. aeruginosa and the applied aspects probably scaled up to design promising lead molecules toward these pathogens. Communicated by Ramaswamy H. Sarma.

Potential inhibitors for peroxiredoxin 6 of W. bancrofti: A combined study of modelling, structure-based drug design and MD simulation

Non-small cell lung cancer (NSCLC) is an obscure disease whose incidence is increasing worldwide day by day, and PI3Kα is one of the major targets for cell proliferation due to the mutation. Since PI3K is a class of kinase enzyme, and no in silico research has been performed on the inhibition of PI3Kα mutation by small molecules, we have selected the protein kinase inhibitor database and performed the energy minimization process by ligand preparation. The key objective of this research is to identify the potential hits from the protein kinase inhibitor library and further to perform lead optimization by a molecular docking and dynamics approach. And so, the protein was selected (PDB ID: 4JPS), having a unique inhibitor and a specific binding pocket with amino acid residue for the inhibition of kinase activity. After the docking protocol validation, structure-based virtual screening by molecular docking and MMGBSA binding affinity calculations were performed and a total of ten hits were reported. Detailed analysis of the best scoring molecules was performed with ADMET analysis, induced fit docking (IFD) and molecular dynamics (MD) simulation. Two molecules – 6943 and 34100 – were considered lead molecules and showed better results than the PI3K inhibitor Copanlisib in the docking assessment, ADMET analysis, and molecular dynamics simulation. Furthermore, the synthetic accessibility of the two compounds – 6943 and 34100 – was investigated using SwissADME, and the two lead molecules are easier to synthesize than the PI3K inhibitor Copanlisib. Computational drug discovery tools were used for identification of kinase inhibitors as anti-cancer agents for NSCLC in the present research.

Response regulator GacA and transcriptional activator RhlR proteins involved in biofilm formation of Pseudomonas aeruginosa are prospective targets for natural lead molecules: Computational modelling, molecular docking and dynamic simulation studies

Gonorrhea, one of the sexually transmitted disease caused by a gram negative diplococcus bacteria Neisseria gonorrhoeae. Rho protein is indispensable for bacterial viability due to its versatile functions in physiology apart from RNA dependent transcription termination. Based on conserved function and wider role in several cellular processes, inhibitors specifically targeting Rho proteins are largely in use these days to treat various bacterial infections. In this study, three dimensional structure of Rho protein was modeled using the template protein from E. coli and further the optimized model was simulated for 100 ns to understand the structural stability and compactness. Owing to the therapeutic potential of Rho, traditional structure-based virtual screening was applied to identify potential inhibitors for the selected target. Based on empirical glide scoring functions two potent lead molecules (ChemBridge_6121956 and ChemBridge_5232688) were selected from ChemBridge database. The pharmacokinetic properties of these lead molecules are within the permissible range. DFT descriptor revealed that the lead molecules are more reactive, which also supports the molecular docking studies. The stability of Rho and Rho-inhibitor complexes was studied using molecular dynamics simulation. Parameters include binding free energy calculation, RMSD, RMSF and hydrogen bond analysis depicts the stability of Rho and Rho-inhibitors throughout the simulation. Altogether, the identified lead molecules require further optimization towards the design and development of new antibiotics against N. gonorrhoeae. Communicated by Ramaswamy H. Sarma

Interleukin-4-induced gene 1 (IL4I1) is an L-phenylalanine oxidase. As the primary enzyme responsible for degrading tryptophan, IL4I1 generates indole metabolites and kynurenic acid, which act as crucial endogenous ligands to activate the aryl hydrocarbon receptor (AHR). This activation enhances tumor survivability while suppressing the body’s anti-tumor immune response. Consequently, IL4I1 is now recognized as a promising new target for drug development in the realm of cancer immunomodulation. In this study, we employed a strategy combining AlphaFold2 with molecular dynamics (MD) simulations to model receptor conformations our docking model achieved a regression fit with an R2 coefficient of 0.34, providing a robust framework for structure-based virtual screening aimed at identifying potential IL4I1 inhibitors. We then applied this structure-based virtual screening method to a compound library. After further MD simulation and following Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculation of binding free energy and ADMET analysis, five candidate IL4I1 inhibitors were obtained. This study provides an effective in silico approach for the identification of IL4I1 inhibitors and offers a valuable reference for the virtual screening of inhibitors targeting other proteins without known structures.

Snake venom metalloproteinase (SVMP) (Echis coloratus (Carpet viper) is a multifunctional enzyme that is involved in producing several symptoms that follow a snakebite, such as severe local hemorrhage, nervous system effects and tissue necrosis. Because the three-dimensional (3D) structure of SVMP is not known, models were constructed, and the best model was selected based on its stereo-chemical quality. The stability of the modeled protein was analyzed through molecular dynamics (MD) simulation studies. Structure-based virtual screening was performed, and 15 potential molecules with the highest binding energies were selected. Further analysis was carried out with induced fit docking, Prime/MM–GBSA (ΔGBind calculations), quantum-polarized ligand docking, and density functional theory calculations. Further, the stability of the lead molecules in the SVMP-active site was examined using MD simulation. The results showed that the selected lead molecules were highly stable in the active site of SVMP. Hence, these molecules could potentially be selective inhibitors of SVMP. These lead molecules can be experimentally validated, and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for snake antivenom.

PARP1 (poly ADP-ribose polymerase 1, also known as ADPRT1) plays a significant role in DNA repair and has become an attractive target for treating PARP1-related diseases, such as cancer. This study aimed to discover inhibitors targeting PARP1 from the phytochemicals of Huangbai (Phellodendron chinense Schneid.), Baixianpi (Dictamnus dasycarpus Turcz.), and Shechuangzi (Cnidium monnieri (L.) Spreng.). The chemical compositions of Huangbai, Baixianpi, and Shechuangzi were extracted from the HERB database. Next, a combination of molecular docking and PARP1 enzyme assay was used to identify PARP1 inhibitors from these chemical components. Finally, molecular dynamics simulation and binding free energy calculation were used to explore the detailed interaction mode of these inhibitors with PARP1. A total of 507 chemical constituents of Huangbai, Baixianpi, and Shechuangzi were collected from the HERB database. Four potential PARP1 inhibitors were screened based on molecular docking and PARP1 enzyme assay. Demethyleneberberine exhibited strong PARP1 inhibitory activity with an IC50 value of 2.0 ± 0.8 μM. The IC50 values of the inhibitory activities of 8-hydroxy dictanmnine, meranzin hydrate, and osthol on PARP1 ranged from 44 μM to 76 μM. Molecular dynamics simulation and binding free energy calculation suggested that the nonpolar interaction energies of HIS862, GLY863, TYR889, TYR896, PHE897, and TYR907 played a primary role in the binding of inhibitors to PARP1. Integrating molecular simulation and bioactivity testing was found to be an effective approach for the rapid discovery of targeted PARP1 inhibitors. Demethyleneberberine demonstrated strong PRAP1 inhibitory activity and has a good prospect for development.

Antibiotic resistance is a critical global health issue, and Pseudomonas aeruginosa is a particularly challenging pathogen. This gram-negative bacterium is notorious for its high virulence and resistance to antimicrobial agents, making it a leading cause of nosocomial infections, significantly impacting public health. The adaptability and multidrug resistance of P. aeruginosa exacerbate treatment difficulties, resulting in increased morbidity and mortality rates worldwide. Consequently, targeting bacterial quorum sensing (QS) systems is a promising strategy for the development of novel antimicrobial compounds against this resilient pathogen. In this study, a structure-based virtual screening (SBVS) approach was employed to identify marine natural products (MNPs) as potential lead molecules targeting the biofilm-forming PqsR protein of P. aeruginosa. A total of ~37,000 MNPs were initially evaluated and ranked based on docking scores using high-throughput virtual screening (HTVS), Standard Precision (SP), and Extra Precision (XP) methods. Ten lead molecules (five from the CMNPD database and five from the MNPD database) were shortlisted based on their docking scores (<-10.0 kcal/mol) and binding free energy values (MM-GBSA ΔG <-40 kcal/mol). Their drug-likeness profiles were assessed using stringent criteria in the QikProp module of Schrödinger, and their chemical reactivity was evaluated through density functional theory (DFT) calculations. The structural and energetic interactions between the identified MNPs and the PqsR-binding pocket were validated through molecular dynamics simulations (MDS) and binding free energy (BFE) calculations. Structural dynamic analyses revealed that the MNP-bound PqsR complexes demonstrated stable interactions within the binding pocket, with hydrophobic residues such as L208, I236, and I263 playing a crucial role in maintaining stability. Among the identified MNPs, CMNPD14329, CMNPD23880, MNPD13399, and MNPD13725 emerged as promising lead molecules for further research. These candidates can serve as foundations for developing structural analogs with enhanced binding affinities for PqsR and other biofilm-forming proteins. Further experimental validation is essential to confirm the therapeutic potential of these identified MNPs.

The emergence of SARS-CoV-2 in December 2019 has become a global issue due to the continuous upsurge in patients and the lack of drug efficacy for treatment. SARS-CoV-2 3CLPro is one of the most intriguing biomolecular targets among scientists worldwide for developing antiviral drugs due to its relevance in viral replication and transcription. Herein, we utilized computer-assisted drug screening to investigate 326 natural products from Thai traditional plants using structure-based virtual screening against SARS-CoV-2 3CLPro. Following the virtual screening, the top 15 compounds based on binding energy and their interactions with key amino acid Cys145 were obtained. Subsequently, they were further evaluated for protein-ligand complex stability via molecular dynamics simulation and binding free energy calculation using molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approaches. Following drug-likeness and ADME/Tox assessments, seven bisbenzylisoquinolines were obtained, including neferine (3), liensinine (4), isoliensinine (5), dinklacorine (8), tiliacorinine (13), 2'-nortiliacorinine (14), and yanangcorinine (15). These compounds computationally showed a higher binding affinity than native N3 and GC-373 inhibitors and attained stable interactions on the active site of 3CLpro during 100 ns in molecular dynamics (MD) simulation. Moreover, the in vitro enzymatic assay showed that most bisbenzylisoquinolines could experimentally inhibit SARS-CoV-2 3CLPro. To our delight, isoliensinine (5) isolated from Nelumbo nucifera demonstrated the highest inhibition of protease activity with the IC50 value of 29.93 μM with low toxicity on Vero cells. Our findings suggested that bisbenzylisoquinoline scaffolds could be potentially used as an in vivo model for the development of effective anti-SARS-CoV-2 drugs.

The bacterium Bacillus coagulans has attracted interest because of its ability to produce spores and advantageous probiotic traits, such as facilitating food digestion in the intestine, managing some disorders, and controlling the symbiotic microbiota. Spore-forming probiotic bacteria are especially important in the probiotic industry compared to non-spore-forming bacteria due to their stability during production and high resistance to adverse factors such as stomach acid. When spore-forming bacteria are exposed to environmental stresses, they enter the sporulation pathway to survive. This pathway is activated by the final phosphorylation of the master regulator of spore response, Spo0A, and upon achieving the phosphorylation threshold. Spo0A is indirectly inhibited by some enzymes of the aspartate response regulator phosphatase (Rap) family, such as RapJ. RapJ is one of the most important Rap enzymes in the sporogenesis pathway, which is naturally inhibited by the pentapeptides. This study used structure-based virtual screening and molecular dynamics (MD) simulation studies to find potential RapJ hits that could induce the sporulation pathway. The crystal structures of RapJ complexed with pentapeptide clearly elucidated their interactions with the enzyme active site. Based on the binding compartment, through molecular docking, MD simulation, hydrogen bonds, and binding-free energy calculations, a series of novel hits against RapJ named tandutinib, infigratinib, sitravatinib, linifanib, epertinib, surufatinib, and acarbose were identified. Among these compounds, acarbose obtained the highest score, especially in terms of the number of hydrogen bonds, which plays a major role in stabilizing RapJ-ligand complexes, and also according to the occupancy percentages of hydrogen bonds, its hydrogen bonds were more stable during the simulation time. Consequently, acarbose is probably the most suitable hit for RapJ enzyme. Notably, experimental validation is crucial to confirm the effectiveness of the selected ligands.

Epidermal growth factor receptor (EGFR) is a transmembrane protein belonging to the receptor tyrosine kinase (RTK) superfamily, reported as a promising anticancer target in treating diverse malignancies. Previous studies on microarray gene expression and methylation status in cell and animal models revealed the differential expression of EGFR at the early stages of cellular transformation. Additionally, an unpublished study of methylation analysis of EGFR gene promoters conducted in human cancer-related samples showed a several-fold increase in EGFR gene expression, suggesting epigenetic upregulation in tumors. Considering these findings, in the present study, we selected inactive (DFGout) (D: aspartic acid, F: phenylalanine, G: glycine) and active (DFGin) confirmations of EGFR to identify novel lead molecules against aberrant EGFR activity in cancer. Extra precision (XP) docking, molecular mechanics/generalized born surface area (MM/GBSA), molecular dynamics (MD) simulations, and ADME/T were performed, and the results showed that the lead 1 molecule of each target exhibited a better binding affinity and favorable stability than the existing ligands.

Lymphatic filariasis, or elephantiasis, is a neglected tropical disease caused by filarial nematodes such as Brugia malayi. Current antifilarial drugs-diethylcarbamazine (DEC), albendazole, and ivermectin form the basis of mass drug administration (MDA) programs for lymphatic filariasis. While effective against microfilarial stages, these agents show little or no macrofilaricidal activity, necessitating repeated treatment rounds to interrupt transmission. Growing evidence of reduced efficacy and emerging resistance further threatens the sustainability of these regimens. Thioredoxin reductase (TrxR) and β-tubulin are critical for parasite survival: TrxR maintains redox balance and protects against oxidative stress, while β-tubulin supports cytoskeletal integrity, intracellular transport, and cell division. Their combined roles in stress adaptation and structural stability make them compelling dual targets. This study employed structure-based virtual screening, molecular docking, and molecular dynamics simulations (MDS) to identify novel thiol-based inhibitors against both proteins. A total of 467 compounds were virtually screened, leading to the identification of seven lead candidates with superior docking scores (- 8.5 to - 4.0kcal/mol) compared to the standard drug albendazole (- 5.3 to - 4.5kcal/mol). Notably, compound 15 demonstrated the strongest binding affinity coupled with an optimal toxicity profile. Pharmacokinetic analysis using ADME assays confirmed drug-likeness and oral bioavailability of the top ligands, with minimal Lipinski's rule violations. Molecular dynamics simulations exceeding 100 ns revealed sustained stability of the protein-ligand complex, which was further supported by RMSD and RMSF analyses, demonstrating conformational stability. Principal interactions comprised hydrogen bonding, hydrophobic contacts, and π-stacking with conserved residues within the active sites of the target proteins. The integrated in silico approach combining docking, pharmacokinetic profiling, and MDS successfully identified potent thiol-based ligands with high affinity for β-tubulin and TrxR in B. malayi. Among these, HI/CYR/TH-15 emerged as the most promising lead. These findings provide a foundation for the development of next-generation anti-filarial therapies targeting multiple life stages, warranting further in vitro and in vivo validation to confirm therapeutic potential. The online version contains supplementary material available at 10.1007/s40203-025-00474-7.

Microtubule stabilizers provide an important mode of treatment via mitotic cell arrest of cancer cells. Recently, we reported two novel neolignans derivatives Cmp10 and Cmp19 showing anticancer activity and working as microtubule stabilizers at micromolar concentrations. In this study, we have explored the binding site, mode of binding, and stabilization by two novel microtubule stabilizers Cmp10 and Cmp19 using in silico molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations. Molecular docking studies were performed to explore the β-tubulin binding site of Cmp10 and Cmp19. Further, MD simulations were used to probe the β-tubulin stabilization mechanism by Cmp10 and Cmp19. Binding affinity was also compared for Cmp10 and Cmp19 using binding free energy calculations. Our docking results revealed that both the compounds bind at Ptxl binding site in β-tubulin. MD simulation studies showed that Cmp10 and Cmp19 binding stabilizes M-loop (Phe272-Val288) residues of β-tubulin and prevent its dynamics, leading to a better packing between α and β subunits from adjacent tubulin dimers. In addition, His229, Ser280 and Gln281, and Arg278, Thr276, and Ser232 were found to be the key amino acid residues forming H-bonds with Cmp10 and Cmp19, respectively. Consequently, binding free energy calculations indicated that Cmp10 (−113.655 kJ/mol) had better binding compared to Cmp19 (−95.216 kJ/mol). This study provides useful insight for better understanding of the binding mechanism of Cmp10 and Cmp19 and will be helpful in designing novel microtubule stabilizers.

Infective endocarditis (IE) is a serious form of microbial infection of the endocardial surface, lining of the heart chambers and heart valves with a high mortality rate. Through comparative genomics, subtractive genomics, and metabolic pathway analysis, 18 common drug targets were identified (Priyadarshini et al., 2013). In the present study, β-Ketoacyl-acyl carrier protein synthase III (FabH), a common protein among eight selected pathogens of IE, was selected for the study. FabH catalyzes the initiation of fatty acid elongation by condensing malonyl-ACP with acetyl-CoA. FabH is an essential enzyme for bacterial viability, because of its pivotal roles in both initiation and regulation of the fatty acid biosynthesis. Experimentally determined tertiary structure of FabH of Streptococcus mitis (reference organism) was not reported yet. Therefore, molecular modeling of FabH in complex with 2-({[4-bromo-3-(diethylsulfamoyl) phenyl] carbonyl} amino) benzoic acid (B82) was constructed using Modeller9v10 (Figure 1). An in-house library consisting of 23969 structural analogs from 60 available FabH inhibitors was compiled from Ligand.Info database. Structure-based virtual screening was performed through three-stage docking technique (HTVS, SP, and XP) using Glide v5.7 led to identification of seven lead molecules with better binding affinity compared to published inhibitor (XP Gscore −8.268 kcal/mol). Lead1 showed the lowest XP Gscore of −9.953 kcal/mol with strong binding interactions with FabH. Molecular dynamic (MD) simulations (Priyadarshini et al., 2011) for FabH–lead1 docking complex were performed using Desmond v3.0 for 10 ns. It revealed that the complex (Figure 1) remained structurally and energetically stable in all 2084 trajectories. The docking interactions were also reproduced during MD simulations. Therefore, lead1 would be a potent inhibitor of FabH and ideal for designing drug for IE.