Structural investigations into the binding mode of novel neolignans Cmp10 and Cmp19 microtubule stabilizers by in silico molecular docking, molecular dynamics, and binding free energy calculations

In recent years, short peptide self-assembled materials, prepared under the control of the thermolysin catalyst, have been investigated extensively and shown to acquire various morphologies and fun...

Staphylococcus aureus MurE enzyme catalyzes the addition of l-lysine as third residue of the peptidoglycan peptide moiety. Due to the high substrate specificity and its ubiquitous nature among bacteria, MurE enzyme is considered as one of the potential target for the development of new therapeutic agents. In the present work, induced fit docking (IFD), binding free energy calculation, and molecular dynamics (MD) simulation were carried out to elucidate the inhibition potential of 2-thioxothiazolidin-4-one based inhibitor 1 against S. aureus MurE enzyme. The inhibitor 1 formed majority of hydrogen bonds with the central domain residues Asn151, Thr152, Ser180, Arg187, and Lys219. Binding free-energy calculation by MM-GBSA approach showed that van der Waals (ΔGvdW, −57.30 kcal/mol) and electrostatic solvation (ΔGsolv, −36.86 kcal/mol) energy terms are major contributors for the inhibitor binding. Further, 30-ns MD simulation was performed to validate the stability of ligand–protein complex and also to get structural insight into mode of binding. Based on the IFD and MD simulation results, we designed four new compounds D1–D4 with promising binding affinity for the S. aureus MurE enzyme. The designed compounds were subjected to the extra-precision docking and binding free energy was calculated for complexes. Further, a 30-ns MD simulation was performed for D1/4C13 complex.

In silico exploration of aryl sulfonamide analogs as voltage-gated sodium channel 1.7 inhibitors by using 3D-QSAR, molecular docking study, and molecular dynamics simulations

The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.

In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD) simulation and binding free energy (ΔGbind) calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds) in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA), and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors.

The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin-3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40-ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC50 values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors.

Free Energy Calculations of Sparsomycin Analogs Binding to the Ribosome with Molecular Dynamics Simulations

Traditional Chinese Medicine Luo Tong Formula attenuates retinal injury in experimental diabetic retinopathy via modulation of DNA methylation: in vivo experiment integrated with molecular docking, ADMET assessment, and molecular dynamics simulation

The p300/CBP associated factor bromodomain (PCAF Brd) is emerged as one of the promising target proteins for different types of cancers. PCAF is one among the histone acetyltransferase enzymes which involved in the regulation of transcriptase process by modifying the chromatin structure. Anacardic acid, carnosol, garcinol are the experimentally reported inhibitors of PCAF Brd; however, their detailed binding mechanism these inhibitors are not yet known. The intermolecular interaction, binding energy, and the stability of these inhibitors with the active site of PCAF Brd are playing the key role in the binding of these inhibitors with PCAF. The in silico study incorporates the molecular docking and dynamics simulations; these molecular level simulations allow to understand the binding mechanism. In the present study, the induced fit molecular docking and molecular dynamics of anacardic acid, carnosol and garcinol molecules against the PCAF Brd have been performed. The docking score values of these molecules are -5.112 (anacardic acid), -5.141 (carnosol), -5.199 (garcinol) and -3.641 (L45) kcal/mol, respectively. Further, the molecular dynamics simulation was carried out for these docked complexes to understand their conformational their stability and binding energy from the roots means square deviation (RMSD) and root means square of fluctuation (RMSF), and molecular mechanics with the generalized born and surface area solvation (MM/GBSA) binding free energy calculations. The intermolecular interactions and binding free energy values confirm that garcinol forms key interactions and has high binding affinity towards PCAF Brd on compare with the other two inhibitors. Therefore, garcinol may be considered as a potential inhibitor of PCAF Brd.

Objective: This study explored the potential of dietary polyphenols from whole green jackfruit flour as natural Sodium-Glucose Co-Transporter-2 (SGLT-2) inhibitors for managing hyperglycemia in diabetes mellitus. Methods: Advanced bio-computational techniques, including molecular docking, Molecular Dynamics (MD) simulations, and binding free energy calculations, were employed to identify and assess polyphenols from jackfruit flour. Caffeic and syringic acids were highlighted for their strong binding affinities to the SGLT-2 receptor. Additionally, a ligand-based pharmacophore model was developed using caffeic acid as a reference to screen for new lead compounds in commercial and natural product databases. Results: The study found that caffeic acid and syringic acid exhibited stronger binding affinities and more stable interaction profiles with the SGLT-2 receptor than the standard drug empagliflozin. MD simulations demonstrated that these compounds provided greater stability in the binding site, indicating their potential efficacy as SGLT-2 inhibitors. The pharmacophore screening further supported these findings, identifying both compounds as promising lead candidates. Among the 14 dietary polyphenols obtained from High-Performance Liquid Chromatography (HPLC), a molecular docking study suggested that caffeic acid (binding affinity:-9.0 kcal/mol) and syringic acid (binding affinity:-9.1 kcal/mol) exhibited stronger binding affinities and more stable interaction profiles with the SGLT-2 receptor compared to the standard drug empagliflozin (binding affinity:-10.4 kcal/mol). Further, molecular dynamics simulations demonstrated that these compounds provided greater stability in the binding site, indicating their potential efficacy as SGLT-2 inhibitors through Root mean Square Deviation (RMSD), Root mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), and ligand hydrogen bonds. The pharmacophore screening further supported these findings, identifying both compounds as promising lead candidates. Conclusion: This study is the first to identify caffeic acid and syringic acid from whole green jackfruit flour as effective SGLT-2 inhibitors. These natural compounds show significant potential as novel agents for managing hyperglycemia and diabetes mellitus. The findings support further exploration of plant-derived therapies in diabetes treatment.

Monoamine oxidase B (MAO-B) serves as a critical target in the management of neurodegenerative diseases (NDDs) such as Alzheimer’s and Parkinson’s due to its role in regulating oxidative stress and dopamine metabolism. In this context, phytochemicals from Oxalis species, known for their neuroprotective properties, were explored for their potential MAO-B inhibitory activity using computational approach. Plant-derived compounds, offering a better safety profile than synthetic drugs and greater cost-effectiveness, present a promising avenue for developing alternative therapeutic strategies. Molecular docking (MD), molecular dynamics simulations (MDS), and binding free energy calculations were employed to evaluate the inhibitory potential of Oxalis phytochemicals against MAO-B (PDB ID: 4A79). Stable ligand-protein complexes with optimal docking scores were selected, and key parameters from molecular dynamics trajectories, including binding stability and interactions, were analyzed to identify high potential inhibitors of MAO-B for therapeutic development. Results showed beta-sitosterol (−11.92 kcal/mol), squalene (−11.89 kcal/mol), etretinate (−11.46 kcal/mol), rhoifolin (−11.44 kcal/mol), and swertisin (−11.13 kcal/mol) demonstrated superior binding affinities compared to the native ligand (−11.12 kcal/mol). Three additional compounds; phloridzin (−11.10 kcal/mol), rhapontin (−11.02 kcal/mol), and diosmetin 7-O-beta-D-glucopyranoside (−10.96 kcal/mol) exhibited better binding than reference drugs. The predominant interactions between protein and ligand were hydrophobic, with hydrogen bonds and Pi-stacking enhancing the complexes’ stability. The evaluation based on geometrical and thermodynamic metrics derived from 200 ns MDS, identified rhoifolin, beta-sitosterol, and swertisin as promising MAO-B inhibitors. Minimal translational and rotational movements of these ligands within the catalytic site of MAO-B under quasi-physiological conditions suggested effective inhibition. Preserved thermodynamic feasibility reinforced these findings. ADMET analysis identified squalene and beta-sitosterol as CNS active candidates with favorable pharmacokinetics, while etretinate, rhoifolin, and swertisin may act as peripheral modulators, requiring optimization for improved CNS delivery. Further experimental validation of efficacy, pharmacokinetics, and safety is recommended to advance the therapeutic potential of these hit candidates.

Monoamine oxidase B (MAO-B) serves as a critical target in the management of neurodegenerative diseases (NDDs) such as Alzheimer’s and Parkinson’s due to its role in regulating oxidative stress and dopamine metabolism. In this context, phytochemicals from Oxalis species, known for their neuroprotective properties, were explored for their potential MAO-B inhibitory activity using computational approach. Plant-derived compounds, offering a better safety profile than synthetic drugs and greater cost-effectiveness, present a promising avenue for developing alternative therapeutic strategies. Molecular docking (MD), molecular dynamics simulations (MDS), and binding free energy calculations were employed to evaluate the inhibitory potential of Oxalis phytochemicals against MAO-B (PDB ID: 4A79). Stable ligand-protein complexes with optimal docking scores were selected, and key parameters from molecular dynamics trajectories, including binding stability and interactions, were analyzed to identify high potential inhibitors of MAO-B for therapeutic development. Results showed beta-sitosterol (−11.92 kcal/mol), squalene (−11.89 kcal/mol), etretinate (−11.46 kcal/mol), rhoifolin (−11.44 kcal/mol), and swertisin (−11.13 kcal/mol) demonstrated superior binding affinities compared to the native ligand (−11.12 kcal/mol). Three additional compounds; phloridzin (−11.10 kcal/mol), rhapontin (−11.02 kcal/mol), and diosmetin 7-O-beta-D-glucopyranoside (−10.96 kcal/mol) exhibited better binding than reference drugs. The predominant interactions between protein and ligand were hydrophobic, with hydrogen bonds and Pi-stacking enhancing the complexes’ stability. The evaluation based on geometrical and thermodynamic metrics derived from 200 ns MDS, identified rhoifolin, beta-sitosterol, and swertisin as promising MAO-B inhibitors. Minimal translational and rotational movements of these ligands within the catalytic site of MAO-B under quasi-physiological conditions suggested effective inhibition. Preserved thermodynamic feasibility reinforced these findings. ADMET analysis identified squalene and beta-sitosterol as CNS active candidates with favorable pharmacokinetics, while etretinate, rhoifolin, and swertisin may act as peripheral modulators, requiring optimization for improved CNS delivery. Further experimental validation of efficacy, pharmacokinetics, and safety is recommended to advance the therapeutic potential of these hit candidates.

The NS5B RdRp polymerase is a prominent enzyme for the replication of Hepatitis C virus (HCV). During the HCV replication, the template RNA binding takes place in the “fingers” sub-domain of NS5B. The “fingers” domain is a new emerging allosteric site for the HCV drug development. The inhibitors of the “fingers” sub-domain adopt a new antiviral mechanism called RNA intervention. The details of essential amino acid residues, binding mode of the ligand, and the active site intermolecular interactions of RNA intervention reflect that this mechanism is ambiguous in the experimental study. To elucidate these details, we performed molecular docking analysis of the fingers domain inhibitor quercetagetin (QGN) with NS5B polymerase. The detailed analysis of QGN-NS5B intermolecular interactions was carried out and found that QGN interacts with the binding pocket amino acid residues Ala97, Ala140, Ile160, Phe162, Gly283, Gly557, and Asp559; and also forms π⋯π stacking interaction with Phe162 and hydrogen bonding interaction with Gly283. These are found to be the essential interactions for the RNA intervention mechanism. Among the strong hydrogen bonding interactions, the QGN⋯Ala140 is a newly identified important hydrogen bonding interaction by the present work and this interaction was not resolved by the previously reported crystal structure. Since D559G mutation at the fingers domain was reported for reducing the inhibition percentage of QGN to sevenfold, we carried out molecular dynamics (MD) simulation for wild and D559G mutated complexes to study the stability of protein conformation and intermolecular interactions. At the end of 50 ns MD simulation, the π⋯π stacking interaction of Phe162 with QGN found in the wild-type complex is altered into T-shaped π stacking interaction, which reduces the inhibition strength. The origin of the D559G resistance mutation was studied using combined MD simulation, binding free energy calculations and principal component analysis. The results were compared with the wild-type complex. The mutation D559G reduces the binding affinity of the QGN molecule to the fingers domain. The free energy decomposition analysis of each residue of wild-type and mutated complexes revealed that the loss of non-polar energy contribution is the origin of the resistance.Communicated by Ramaswamy H. Sarma

Syzygium aromaticum (L.) Merr. & L.M. Perry is a known spice with a high phytochemical content that can be explored in drug discovery. We investigated the in vitro enzyme inhibitory activities of a flavonoid-rich extract of S. aromaticum (FRESA) against type II diabetes (T2D) and Alzheimer’s disease (AD) and identified its anti-T2D and anti-AD phytochemicals via computational prediction. The in vitro enzyme inhibitory activities of a flavonoid-rich extract of Syzygium aromaticum were evaluated via standard protocols following flavonoid-enriched extraction procedures. High-performance liquid chromatography (HPLC) was employed to characterize the constituent bioactive flavonoids. Molecular docking of eight phytochemicals was performed via AutoDock Vina in PyRx 0.8, which identified apigenin, myricetin, and quercetin as hit compounds with high binding affinities and multitarget activities against α-amylase, α-glucosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO). Molecular dynamics simulations (100 ns) were conducted via GROMACS 2019.2, and binding free energy calculations were performed via the MM-GBSA approach to validate the stability and interaction integrity of the hit phytochemicals. FRESA (IC50 = 961.943 ± 21.031 μg/mL) exhibited moderate activity against α-amylase compared with that of acarbose (IC50 = 27.104 ± 0.270 μg/mL). Compared with acarbose (IC50 = 17.389 ± 0.436 μg/mL), FRESA had appreciable activity against α-glucosidase (IC50 = 562.045 ± 6.714 μg/mL). FRESA demonstrated significant (p < 0.0001) inhibition of acetylcholinesterase (IC50 = 26.911 ± 0.058 µg/mL), surpassed galantamine (IC50 = 27.950 ± 0.122 µg/mL), and moderately inhibited butyrylcholinesterase (IC50 = 28.168 ± 0.702 µg/mL) to galantamine (IC50 = 23.126 ± 0.683 µg/mL). FRESA also significantly suppressed monoamine oxidase activity in Fe2⁺-induced brain damage in a concentration-dependent manner. HPLC–DAD analysis identified apigenin, caffeic acid, ferulic acid, gallic acid, kaempferol, myricetin, quercetin, and syringic acid as major constituents. Molecular docking revealed apigenin, myricetin, and quercetin as top-ranked multitarget inhibitors, exhibiting strong binding affinities (− 9.0 to − 10.2 kcal/mol) comparable to those of reference inhibitors across α-amylase, α-glucosidase, AChE, BChE, and MAO. Molecular dynamics simulations and MM-GBSA confirmed the binding strength of the hit phytoconstituents in the active pockets of α-amylase, α-glucosidase, AChE, BChE, and MAO, with multitargeting inhibitory activities supporting the in vitro and ex vivo enzyme activities. ADMET profiling indicated favorable drug likeness for apigenin, whereas myricetin and quercetin displayed acceptable pharmacokinetic properties with minimal violations. Our findings provide scientific validation of the anti-T2D and anti-AD properties of S. aromaticum and identify apigenin, myricetin, and quercetin, which could be used for the development of inhibitors of α-amylase, α-glucosidase, AChE, BChE, and MAO as dual therapies to combat T2D and AD. Additional in vivo validation is recommended to ensure a thorough assessment in the present research.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-026-45482-5.

Apoptosis signal-regulating kinase 1 (ASK1), a key component of the mitogen-activated protein kinase (MAPK) cascades, has been identified as a promising therapeutic target owing to its critical role in signal transduction pathways. In this study, we proposed novel pyridin-2-yl urea inhibitors exhibiting favorable physicochemical properties. The potency of these compounds was validated through in vitro protein bioassays. The inhibition (IC50) of compound 2 was 1.55 ± 0.27 nM, which was comparable to the known clinical inhibitor, Selonsertib. To further optimize the hit compounds, two possible binding modes were initially predicted by molecular docking. Absolute binding free energy (BFE) calculations based on molecular dynamics simulations further discriminated the binding modes, presenting good tendency with bioassay results. This strategy, underpinned by BFE calculations, has the great potential to expedite the drug discovery process in the targeting of ASK1 kinase.