In silico pharmacology最新文献

Abstract: Plants have been valuable sources of bioactive compounds with therapeutic potential. The exploration of phytochemicals in plant extracts and essential oils has gained attention due to their biological activities and medicinal properties. This study investigated the phytochemicals in methanolic extracts and essential oils by analysing molecular docking and toxicological profiles of their bioactive and pharmacokinetic properties. Molecular docking using AutoDock Vina, integrated within PyRx version 0.8, was employed to dock the chemicals into the MMP-9 protein 1L6J. Among these, the highest-scoring compounds underwent pharmacokinetics, receptor-ligand interactions, and binding energy (kcal/mol) analysis after identification by GC-MS analysis. To prepare the grid boxes for docking, the active sites of MMP-9 were predicted using CASTp. The findings revealed that several active ingredients in the methanolic extract, particularly 3-fluoro-5-trifluoromethylbenzoic acid, exhibited favourable binding energy (kcal/mol) for MMP-9 and demonstrated molecular interactions such as hydrogen bonding with the key residue TYR 52. Conversely, most interactions formed by the essential oil compounds were hydrophobic. In addition to their biological activity, ADME prediction indicated that both the methanol extract and essential oil possessed adequate drug-likeness characteristics, such as high gastrointestinal absorbability and low permeability through the blood-brain barrier. Based on the toxicological predictions using AdmetSAR 1, the compounds were moderately toxic (class III); however, there were no indications of carcinogenic risk. The observed in silico characteristics of bioactive chemicals derived from E. viscosus suggest potential for wound healing applications, given their favourable pharmacokinetic predictions and predicted MMP-9 binding profiles, warranting further experimental validation.

Graphical abstract:

Snake envenomation remains a major health threat, particularly in rural regions. This study investigates five ethnomedicinal plants Andrographis paniculata, Aristolochia spp., Hemidesmus indicus, Perilla frutescens, and Tabernaemontana catharinensis traditionally used for snakebite treatment in northern Chhattisgarh. Key bioactive compounds, including andrographolide, aristolochic acid, lupeol acetate, rosmarinic acid, and 4-methoxysalicylic acid, and five known compounds 12-methoxy-4 methylvoachalotine, anisic acid, salicylic acid, 1-hydroxytetra triacontan-4-one, and pinostrobin, were evaluated for their interactions with venom protein families PLA2, 3FTx, and KUN using molecular docking via AutoDock Vina. Lupeol acetate exhibited the strongest binding affinity across multiple venom proteins, while 4-methoxysalicylic acid effectively targeted three key domains in the 1VIP protein. Molecular dynamics simulations confirmed the stability of the top protein-ligand complexes. All compounds, except 1-hydroxytetratriacontan-4-one, met Lipinski's and ADMET criteria, indicating favorable drug-like properties. These findings highlight the potential of plant-derived phytochemicals, particularly 4-methoxysalicylic acid, as therapeutic candidates for snakebite treatment. Further experimental validation is recommended to explore their potential as plant-based antidotes.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00488-1.

The global HIV epidemic continues to present significant public health challenges, with millions affected worldwide, necessitating the exploration of novel antiretroviral agents. This study aims to evaluate the inhibitory potential of α-amyrin, a phytochemical from Calotropis procera, against HIV-1 reverse transcriptase (RT) through molecular docking and in vitro assays. The study involved in silico molecular docking to assess the binding affinity of α-amyrin with HIV-1 RT, followed by pharmacokinetic analysis. An in vitro HIV-1 RT inhibition assay was conducted using a colorimetric ELISA kit, with nevirapine as the reference drug. Molecular docking revealed a strong binding affinity of α-amyrin to HIV-1 RT, with a binding energy of -7.33 kcal/mol. The compound formed two hydrogen bonds with key residues (Cys181 and Gln182) in the allosteric binding site. In vitro assays demonstrated dose-dependent RT inhibition, with an IC₅₀ of 26 µg/mL, comparable to nevirapine (IC₅₀ = 21 µg/mL). At the highest concentration (200 µg/mL), α-amyrin achieved 82% inhibition, while nevirapine displayed 92% inhibition. The dual approach combining in silico and in vitro analyses highlights α-amyrin as a promising candidate for HIV-1 RT inhibition. Its strong binding affinity, significant enzymatic inhibition, and favorable pharmacokinetics suggest its potential for further development as a plant-based NNRTI, addressing drug resistance concerns and contributing to improved antiretroviral therapies.

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00498-z.

The COVID-19 pandemic, caused by SARS-CoV-2, requires effective therapeutics targeting the 3-chymotrypsin-like cysteine protease (3CLpro), essential for viral replication. This in-silico study evaluates 12 thiuram disulfides as potential 3CLpro inhibitors. Molecular docking identified DS4, DS6, and DS9 with superior binding affinities (Glide scores: - 5.80, - 5.11, and - 5.17 kcal/mol, respectively) compared to nirmatrelvir (- 4.85 kcal/mol). 100 ns molecular dynamics simulations and MM/PBSA calculations revealed DS6 and DS9 with stronger binding free energies (ΔG: - 34.38 and - 33.27 kcal/mol) than nirmatrelvir (- 21.10 ± 4.59 kcal/mol). Structural analyses (RMSD: 1.80 Å for DS6; RoG: 22.34 Å; RMSF: 7.19 Å) indicated enhanced stability over nirmatrelvir. Per-residue decomposition highlighted key interactions (e.g., HIP41 in DS6: - 46.7 kcal/mol electrostatic). Toxicity predictions via pkCSM showed non-mutagenicity, non-hepatotoxicity, and no skin sensitization. Dynamic cross-correlation analysis suggested allosteric effects influencing conformational flexibility. Thiuram disulfides, especially DS6 and DS9, exhibit promise as 3CLpro inhibitors, warranting further experimental validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00496-1.

PDE-5 enzyme plays a role in penile erection through cGMP hydrolysis in erectile dysfunction (ED), a prevalent urological illness with a complex pathogenesis. To identify potential phytochemical inhibitors targeting the PDE-5 enzyme, along with comparison of final hit with synthetic drug Sildenafil. Lipinski's drug-likeness filter was applied to phytochemicals retrieved from PubChem. These compounds were docked against the PDE-5 using AutoDock Vina and then redocking, followed by ADME/T and toxicity evaluation. A 100 ns MD simulations, and trajectory analyses was done. The electronic properties were assessed using DFT, and the binding free energies were calculated using MM/PBSA. Finally, the results were compared with Sildenafil, a reference drug. A total of 1152 phytochemicals were screened, out of which 515 passed drug-likeness filters. The top 100 compounds based on docking scores (upto - 9.8 kcal/mol) were shortlisted, redocking study suggested RMSD between 1.046 Å. A total 12 compounds showing favourable ADMET profiles, among them, four compounds were chosen for MD simulations. A stable engagement is indicated by RMSD values in the 0.16-0.79 nm range. MM/PBSA analysis revealed strong binding energies (- 17.01 to - 21.42 kcal/mol). Additionally, DFT studies showed HOMO-LUMO gaps between 3.93 and 6.39 eV, supporting electronic stability and potential bioactivity. The phytochemicals Daidzin, Maackiain, Rutecarpin, and Cyclopamine exhibited strong binding affinity with PDE-5, supported by stable MD simulations and favourable MM/PBSA energies. Their electronic stability and drug-like properties highlight their potential as natural PDE-5 enzyme inhibitors for ED management. All compounds have shown comparably equal results with Sildenafil.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00491-6.

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a critical effector in constitutive NF-κB signalling, driving oncogenesis in activated B-cell-like diffuse large B-cell lymphoma. Here, we employed an integrated computational strategy to design and optimize small-molecule MALT1 inhibitors. A statistically validated Quantitative structure-activity relationship model (R² = 0.86, Q² = 0.82, CCC = 0.90) identified descriptors linked to potency, and docking simulations revealed binding affinities between - 8.6 and - 9.6 kcal/mol. Among the MI-2, a selective small-molecule inhibitor of MALT1 analogues, compound 14 combined favourable docking affinity (- 8.9 kcal/mol) with strong pharmacokinetics, which guided rational optimization. The derivative 14f emerged as the most promising scaffold, achieving improved intestinal absorption (96.9%), favourable clearance (0.43 log ml/min/kg), non-mutagenicity, and the strongest binding affinity (- 9.6 kcal/mol). Molecular dynamics simulations confirmed the stability of the 14f-MALT1 complex, with protein backbone RMSD maintained within 3 Å and ligand fluctuations below 1 Å over 100 ns. Collectively, these results highlight compound 14f as a viable lead scaffold for MALT1 inhibition in DLBCL. As this study is purely computational, experimental validation is required to confirm these findings.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00466-7.

Cancer remains one of the leading causes of death worldwide and is characterized by the dysregulation of multiple signalling pathways involved in cell survival, proliferation, differentiation, and migration. Among these, fibroblast growth factor 2 (FGF2) serves as a key regulator that promotes tumor growth and metastasis and is frequently upregulated in several cancers, including glioblastoma, gastric and breast cancer, acute myeloid leukemia, nasopharyngeal carcinoma, and non-small cell lung cancer. Many cancers, such as glioblastoma where FGF2 plays a key role, remain incurable. Cancer's heterogeneity limits treatment efficacy, underscoring the urgent need to develop diverse and more effective therapeutic options. In the present study, structure-based screening was performed with target protein FGF2 using the LEA3D database, where eight FDA-approved drugs, Elbasvir (1), Velpatasvir (2), Daclatasvir (3), Ritonavir (4), Paliperidone Palmitate (5), Saralasin (6), Nystatin (7), and Cobicistat (8), were identified as potential therapeutics capable of interfering with the binding of FGF2 to its receptor (FGFR), thereby blocking downstream oncogenic signalling pathways. This was followed by molecular docking or redocking and molecular dynamics (MD) simulation studies of the identified potential 8 drugs against the crystal structure of FGF2 (PDB ID: 1BFG). Molecular docking study showed Elbasvir (1) to exhibit the strongest binding affinity (-8.1 kcal/mol), followed by Velpatasvir (2) (-7.6 kcal/mol), Daclatasvir (3) (-7.5 kcal/mol), Ritonavir (4) (-6.2 kcal/mol), Paliperidone Palmitate (5) (-5.9 kcal/mol), Saralasin (6) (-5.4 kcal/mol), Nystatin (8) (-5.2 kcal/mol), and Cobicistat (-5.1 kcal/mol). MD simulations further validated the stability of binding between the identified drugs and FGF2, revealing that compounds 1-6 exhibited the most sustained and stable interactions, thereby supporting their potential as effective FGF2 inhibitors. Compound 8 exhibited milder fluctuations compared to compound 7 and demonstrated stable binding during the final phase of the 100 ns MD simulation, beginning around 90 ns. In contrast, compound 7 showed the least stability throughout the simulation. Overall, the study provides mechanistic insights into the molecular interactions between FGF2 and these candidate drugs, highlighting the promising potential of compounds 1-6 and 8 for subsequent in vitro validation in cancer therapeutics.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00495-2.

Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is a neurodegenerative condition characterized by the gradual deterioration of motor neurons in the brain and spinal cord, leading to muscle weakness, difficulty swallowing, speaking, and breathing. The normal ageing process has structural and functional effects on motor neurons, which may contribute to motor neuron pathology in ALS, either directly or indirectly. Although there are a few treatments available for ALS, their efficacy is limited. The objective of this study is to identify and screen potential C9ORF72 Agonists using High Throughput Virtual screening and Molecular Dynamics simulations. Using Edaravone and Riluzole as benchmark molecules, the study evaluated various chemical compounds from different databases against the target. Lead compounds from three databases (Specs_1289, Zinc_67912153 and Enamine_785152) showed binding affinity, stability and pharmacokinetic greater activity which is achieved through ML based tool; concluding that they could be used as a potential agonist for ALS-associated C9ORF72. The complexes have the highest docking scores of - 8.21, - 11.06, and - 6.934 kcal/mol with the lowest binding energy which aids the structural stability of the complex. HOMO and LUMO occupancy of the lead compounds deciphers the energy levels of the compounds with the lowest energy gap which was favorable for the chemical reactivity and chemical inertness of the molecule. Furthermore, ADME and Toxicity analysis of the compounds were evaluated through Machine Learning based tool, pkCSM. MD simulation concluded that the lead complexes showed lesser deviation and fluctuations with the higher number of hydrogen bond interactions which favors the structural stability and biological activity of the complex. This study concluded that the resultant leads from three different chemical libraries were considered as the potential therapeutic option for targeting ALS.

The study presents a comprehensive approach to target prediction for gout (DOID: 13189) through the integration of disease ontology and network-based strategies. A total of 13 proteins associated with gout were identified and analyzed using the STRING database, which visualized protein-protein interactions (PPIs). Cytoscape, enhanced with the CytoHubba plugin, was used to prioritize key proteins, identifying Solute loading carrier family 22 member 12 (SLC22A12) and SLC22A9 genes as the most promising targets based on their high degree of interaction. Sequence alignment of these proteins (Urate Anion Exchanger 1-URAT1 and Organic anion transporter 7-OAT7) revealed significant homology, suggesting that they play complementary roles in uric acid transport and gout pathogenesis. Molecular docking by AutoDock Vina and AutoDock4 of whole Indian Medicinal Plants, Phytochemistry And Therapeutics (IMPPAT) database, Food and Drug Administration (FDA) Approved Drugs revealed three leads from the Woodfordia fruticosa (Heterophylliin A), Arctium lappa (Arctignan D), and Oroxylum indicum (Scutellarein 7-rutinoside) demonstrated strong binding affinities with URAT1 through favorable docking interactions over the best docked Fostemsavir and URAT1 inhibitors (Lesinurad and Benzbromarone) indicating their potential as modulators of uric acid transport. The molecular dynamics simulations (MDS) of URAT1 in membrane environment with the identified compounds by Desmond further supported that all three leads exhibited superior binding stability, binding energy and interaction profiles compared to the existing drugs. The results highlight the potential of these phytochemicals upon further experimental validation as therapeutic agents for gout. This integrative bioinformatics and computational approach provide a robust framework for discovering potent drug target and bioactive compounds with strong potential for effective gout treatment if further validated through in vitro and in vivo assays.

Graphical abstract:

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00476-5.

Type 2 diabetes is a prevalent disease that continues to pose a significant health burden worldwide. Despite the availability of various drugs for its management, the number of diagnoses and mortalities is persistently on the rise. Alpha-glucosidase inhibition has emerged as a promising therapeutic strategy to prevent postprandial hyperglycaemia. One approach in drug discovery is drug repurposing, which involves investigating existing drugs for new therapeutic indications. This study used a three-stage molecular docking approaches to screen the DrugBank database for potential alpha-glucosidase inhibitors against N-terminal maltase glucoamylase (ntMGAM) target. We selected 10 compounds with top docking performance, and rescoring these compounds with MMGBSA calculations produced arbekacin, neamine, and sisomicin with a binding free energy of - 72.13, - 55.14, and - 69.07 kcal/mol, respectively, as the top three compounds. These compounds were subsequently analysed and compared with the standard drug, acarbose for their protein-binding stability using molecular dynamics simulation (MDS) approach. The MDS analysis suggests that sisomicin exhibited the most stable interactions and stronger post-MDS binding free energy with alpha-glucosidase. These findings suggest that sisomicin is a potential inhibitor of alpha-glucosidase, and a novel candidate for drug repurposing in antidiabetic therapy.