In silico pharmacology最新文献

These are two of the most common gynecologic diseases, affecting 15% to 80% of women of childbearing age diseases. The existing treatments, such as hormonal drugs and selective estrogen receptor modulators like raloxifene, have side effects and recurrence, and thus indicate the need for less harmful non-hormonal therapies. Therefore, this study aimed at exploring plant-derived secondary metabolites as potential ESR1 inhibitors by focusing on the identification of natural ligands characterized by high binding affinity and structural stability and by providing preliminary insights into pharmacokinetic and safety aspects via in silico analysis. Forty structurally diverse phytochemicals were docked into the ESR1 ligand-binding pocket using AutoDock Vina and PyRx, with raloxifene as reference. Procyanidin, the top-scoring ligand, was selected for molecular dynamics (MD) simulations (100 ns, GROMACS) under physiological conditions. Structural stability was assessed by RMSD, RMSF, SASA, and radius of gyration (Rg), while ligand retention was evaluated using center-of-mass (COM) and minimum distance analyses. Three independent 10-ns replicates were also performed to ensure reproducibility of MD results. Procyanidin outperformed raloxifene (- 11.1 kcal/mol) and other options like hesperidin and sanguinarine with the strongest binding (- 12.1 kcal/mol). Docking revealed hydrophobic interactions with Leu387 and Ala350 and hydrogen bonding with Glu353 and Arg394. MD simulations confirmed stable ESR1-procyanidin complexes, with constant RMSD and Rg, stable SASA, and limited flexibility of key binding residues. COM and distance analyses established long-term retention of the ligand, supported by hydrophobic and π-stacking over stable hydrogen bond-dominant binding. Binding free energy analysis (MM-PBSA) further verified a spontaneous and favorable interaction (ΔG_total = - 22.66 kJ mol^-1), mainly driven by van der Waals and hydrophobic forces. Procyanidin is a phytochemical lead that shows promise for controlling ESR1 signaling in fibroids and endometriosis as a non-hormonal candidate. Procyanidin emerged as a promising in-silico lead for ESR1 modulation, showing high binding affinity and dynamic stability; nevertheless, further pharmacokinetic, ADMET, and experimental validation are required to substantiate its therapeutic potential.

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Triple-negative breast cancer is an aggressive subtype characterized by the absence of estrogen, progesterone, and HER2 receptors, which renders it insensitive to most conventional therapies. Inhibition of PARP1 has been pointed out as a promising approach for BRCA1/2-mutated cancers due to a synthetic lethality mechanism. This study presents an integrated in-silico drug discovery workflow for the identification of new generation analogues of clinically approved drugs Olaparib and Talazoparib as potential PARP1 inhibitors. Structural analogues were retrieved from the ZINC database, and their affinity was screened by molecular docking. Drug-likeness and ADMET properties of docked analogues were further evaluated. Top candidates were then subjected to MD simulation and MM/GBSA binding free energy calculation to validate interaction stability and pharmacological potential. The combined computational results highlight several leads with a good binding profile, stability, and drug-like properties, thus representing promising therapeutic leads targeting PARP1 in BRCA-mutated TNBC. Overall, this study has underlined the usefulness of integrated in-silico approaches to accelerate the discovery of optimized PARP1 inhibitors for targeted cancer therapy.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00543-x.

Current NSAIDs and chemotherapeutics suffer from significant toxicities and acquired resistance, creating a pressing need for safer agents. Benzotriazole is a "privileged scaffold" for designing novel therapeutics. This study reports the rational design of novel benzotriazole-chalcone analogues as dual-target inhibitors of cyclooxygenase-2 (COX-2) and aromatase, leveraging their established molecular crosstalk in carcinogenesis. Eight novel benzotriazole-chalcone analogues (PM-1 to PM-8) were synthesized and characterized by FTIR, ¹H NMR, ¹³C NMR, and LCMS. A multi-faceted evaluation included in silico ADMET screening (SwissADME/ProTox-III) and molecular docking (Glide XP) against COX-2 (4COX) and aromatase (3EQM). Analogues were then experimentally validated via in vivo carrageenan-induced paw edema assays and ex vivo cytotoxicity screening against the MCF-7 cell line (SRB assay). All analogues demonstrated favorable in silico drug-likeness and high predicted GI absorption. Molecular docking revealed potent COX-2 binding: PM-6 (-10.519 kcal/mol) and (2E)-1-(1H-benzotriazol-1-yl)-3-(4-hydroxy-3-methoxyphenyl)-prop-2-en-1-one (PM-4) (-10.153 kcal/mol) exhibited stronger affinity than Diclofenac (-8.135 kcal/mol). In vivo, PM-4 and (2E)-1-(1H-benzotriazol-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-prop-2-en-1-one (PM-6) produced significant (p < 0.001) paw edema inhibition. Ex vivo, (2E)-1-(1H-benzotriazol-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-prop-2-en-1-one (PM-6) was the most potent, exhibiting 98.2% inhibition of MCF-7 cell growth at 80 µg/mL. This study identifies (2E)-1-(1H-benzotriazol-1-yl)-3-(4-hydroxy-3-methoxyphenyl)-prop-2-en-1-one (PM-4) and (2E)-1-(1H-benzotriazol-1-yl)-3-(3-hydroxy-4-methoxyphenyl)-prop-2-en-1-one (PM-6) as highly promising, dual-action lead compounds. The strong correlation between their potent in silico binding and experimentally-validated biological activities, combined with favorable ADMET profiles, establishes them as strong candidates for further preclinical development.

Breast cancer, a leading cause of global mortality, necessitates novel therapies targeting key drivers like the epidermal growth factor receptor (EGFR). This computational study evaluates nine 4-phenyl-2H-[1,3]thiazino[3,2-a]benzimidazol-2-imine (H-thiazine) derivatives as potential EGFR inhibitors. Using molecular docking, ADMET profiling, molecular dynamics simulations, and binding energy calculations, we identified methyl- and bromine-substituted derivatives as probable candidates that outperform the reference drug Olmutinib in terms of binding affinity, pharmacokinetics, and stability. Although these compounds showed promising bioactivity, in silico toxicity screening indicated potential AMES mutagenicity and hERG-II inhibition, highlighting important safety liabilities. Overall, thiazine derivatives represent viable scaffolds for EGFR-targeted anti-cancer development; however, further optimization and experimental validation, including biochemical assays and genotoxicity testing, are required to confirm their therapeutic potential.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00542-y.

Nitroimidazole-based derivatives serve as fundamental components in the treatment of microbial infections. Metronidazole (MNZ), a synthetic nitroimidazole compound, is widely used as an important antimicrobial agent (AMA). Since the 1950s, MNZ has been a key drug in clinical medicine for treating a number of bacterial and protozoal diseases. It is commonly prescribed for bacterial vaginosis, amoebiasis, trichomoniasis, giardiasis, Clostridioides difficile-related diarrhoea, and anaerobic intra-abdominal infections. However, the use of MNZ as a therapeutic agent is often limited by unfavourable pharmacokinetics and side effects, including nausea, metallic taste, headache, and neurotoxicity (with long-term use). Therefore, our research explored various modified derivatives of MNZ to enhance its pharmacological activity and toxicity profiles. The geometrical characteristics of the analogues were further optimized via density functional theory (DFT) calculations via the B3LYP/6-31G+ (d, p) basis set. Molecular docking studies were conducted against bacterial thymidylate kinase and protozoal DNA, which revealed that most of the derivatives enhanced the ligand-protein binding affinities and favourable interactions at the protein active sites of both targets. Furthermore, a 100 ns molecular dynamics (MD) simulation was performed to evaluate the mode of interaction and stability of the ligand-protein complex under biological conditions. This result indicated that BNZ, SRZ, and EF5 improved the binding stability and dynamic flexibility patterns of these compounds. The pharmacological activity and safety parameters of the analogues were evaluated through ADMET and PASS analyses. Overall, the results revealed that most of the analogues possess favourable physicochemical and pharmacokinetic properties with few side effects. This research could facilitate the further development of BNZ, SRZ, and EF5 as promising candidates for next-generation AMAs, necessitating advanced preclinical evaluations.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00538-8.

Sulfanilamide (SN), a synthetic broad-spectrum antimicrobial that inhibits folic acid synthesis and suppresses bacterial growth. However, long-term use has caused allergic reactions, skin problems, crystalluria, nephrotoxicity, and other side effects. SN has developed resistance, and its associated side effects underscore the urgent need to discover safer alternatives with greater efficacy and reduced toxicity. In this study, we attempted to design new SN derivatives by incorporating various functional groups into their basic structure. Derivative structures were geometrically optimized utilizing density functional theory (DFT) and B3/LYP 6-31G+(d, p) basis set to calculate their physicochemical and spectrochemical properties. Molecular docking and molecular dynamics (MD) simulations were conducted against the dihydropteroate synthase (DHPS) protein (PDB ID: 1AJ2) to predict the binding affinities of analogs and stability at the active site. ADMET and PASS analyses evaluated toxicological and pharmacological profiles. Most of the derivatives showed lower energy gaps (5.14 eV to 5.30 eV) than SN (5.34 eV). All derivatives showed stronger binding affinities (-5.5 to -6.7 kcal mol^-1) compared to SN (-5.4 kcal mol^-1). ADMET results showed good pharmacokinetics, with some derivatives exhibiting higher GI absorption and most falling under toxicity class III. Overall, SN7 (-6.5 kcal/mol), SN17 (-6.6 kcal/mol), and SN18 (-6.7 kcal/mol) have exhibited better performance. Thus, our research reveals that the studied analogs can serve as novel alternatives to SN with superior quality. However, further experimental and biological studies are necessary to validate these theoretical findings and confirm their potential antibacterial efficacy.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00526-y.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has infected millions worldwide, exacerbating global health concerns. However, a dire need for alternative therapies like active ingredients from natural sources. Therefore, QKC, which are active compounds, are being investigated from Maxing Shigan Decoction (MXSGD), a traditional Chinese medicine (TCM) formula widely used for respiratory illnesses and have shown therapeutic potential in treating SARS-CoV-2. This study investigates MXSGD's active compounds, therapeutic proteins, and pharmacological mechanisms. Integrated multiple networking and GO/KEGG pathway enrichment analysis approaches were employed. While individual ingredient effects were studied, the combined efficacy and molecular mechanisms require further exploration. By combination, quercetin-kaempferol (QKC) is hypothesized to be more effective. A systematic pharmacological approach was used to identify compound targets, predict potential targets, and conduct networking analyses. Five networks were constructed and analyzed: (a) compound-known targets, (b) compound-potential targets, (c) QKC-HP PPI, (d) QKC-MH PPI, and (e) QKC-SARS-CoV-2-PPI networks. GO and pathway enrichment analyses revealed that the ingredients target various biological processes and pathways, with QKC combining the properties of quercetin and kaempferol. This study provides valuable insights in comparing quercetin, kaempferol, and QKC and those exploring QKC's synergies and molecular mechanisms for treating SARS-CoV-2.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00515-1.

Dengue fever, transmitted through mosquito vectors, has emerged as a significant health challenge in India over the past twenty years. This infectious epidemic has demonstrated concerning fatality rates and mortality statistics. The primary objective of this investigation was to conduct molecular simulation studies and evaluate the drug-like properties of marine seaweed fucoidan and five synthetic derivatives against dengue virus (DENV) non-structural proteins. The parent fucoidan compound, along with its acetyl, amino, sulfonyl, phosphate, and benzoyl derivatives, underwent molecular docking analysis against DENV4 NS3 Protease-Helicase (2VBC), DENV2 NS2B/NS3 Protease (2FOM), DENV2 Methyltransferase (1L9K), DENV2 Non-Structural protein NS5 (5ZQK), and DENV2 RNA-dependent RNA polymerase (6IZY). The selected non-structural proteins were analyzed through CDOCKER docking methodology, concentrating on binding sites, with binding energies calculated to assess fucoidan derivative effectiveness. The parent fucoidan, acetylated fucoidan, phosphated fucoidan, and benzoylated fucoidan demonstrated the strongest inhibitory potential against all DENV viral proteins, exhibiting binding affinities of - 13 kcal.mol^-1, - 48 kcal.mol^-1, and 43 kcal.mol^-1, respectively. Pharmacokinetic properties and toxicological profiles were evaluated for all fucoidan compounds using the PreADMET web server simulation software. The comprehensive ligand-binding affinity range for fucoidan and its derivatives spanned from - 146 to - 13 kcal.mol^-1. ADMET analysis confirmed that the parent fucoidan and its acetylated, phosphated, and benzoylated derivatives exhibited non-toxic characteristics with favorable lipophilicity profiles. Molecular dynamics simulation analysis through RMSD and RMSF plots, focusing on the optimized 3,4-diphospho fucoidan, revealed hydrogen bonding patterns and substantial hydrophobic interactions with DENV proteins at allosteric binding sites. In summary, this study establishes that 3,4-diphospho fucoidan represents the most promising lead compound with potential anti-dengue properties among all tested derivatives. Therefore, this molecule warrants additional investigation through in vitro experimental studies.

Immunotherapy has garnered significant attention as a promising alternative treatment modality for triple-negative breast cancer because of its immunogenic nature. Of late, the modulation of programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1) has shown potency in combating TNBC. Till date, several monoclonal antibodies and peptides are being used as PD-1/PD-L1 modulators. Nevertheless, the limitations associated with these molecules necessitate the development of potent alternative therapeutics. Thus, the present study aimed to employ a series of virtual screening strategies to derive peptidomimetic molecules as PD-1 modulators. Initially, a short peptide sequence (p-ADKYR) that disrupts the PD-1/PD-L1 dyad was designed. Subsequently, alanine scanning was conducted to analyse the critical residues on the designed peptide. The obtained results were then utilised for screening of peptidomimetics from the pep: MMs: MIMIC. The binding of the 200 peptide-mimicking molecules with the PD-1 protein was determined using AutoDock Vina. Further, the binding free energy and machine learning-based scoring analysis were used to re-score the docked pose of the complexes. Then, interaction analysis and ADMET properties were assessed for the obtained peptidomimetics, which resulted in one molecule, MMs01069049, as a potent PD-1 modulator. Finally, molecular dynamics simulation was performed for 200 ns, and the equilibrated structure from the last 5 ns was subjected to binding free energy analysis using MM-GBSA, which confirmed the enhanced stability and affinity of MMs01069049 at the PD-1 interface compared to the designed peptide. Collectively, we propose that MMs01069049 may serve as an efficient PD-1 modulator for the management of TNBC in the near future.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00528-w.

This study aims to analyze the inhibitory action of the phytochemicals of Hedychium spicatum by computational docking studies, molecular dynamics simulations, and ADMET studies. For this, natural metabolites were taken from the IMPPAT and KNApSAcK databases. The crystallographic structure of the molecular target cyclooxygenase-2 (COX-2) was obtained from the RCSB PDB (PDB ID: 5IKR). Mefenamic acid, a well-known nonsteroidal anti-inflammatory drug (NSAID), was used as the standard for comparative analysis. Computational docking analysis was performed using Schrödinger's Glide, an option based on scoring functions. MD simulations were performed, followed by statistical analysis that included RMSD, RMSF, RoG, and H-bond analysis. MMGBSA analysis revealed optimal binding affinities ([Formula: see text]) with molecular targets HS6428435 (cis-Sesquisabinene hydrate), HS519857 (Cubenol), and HS7439 (Carvone), with values of - 37.32, - 32.20, and - 26.31 kcal/mol, respectively. Notably, HS6428435 exhibits a strong binding affinity of - 37.32 kcal/mol, compared to the standard drug, which has a binding affinity of - 35.28 kcal/mol, making it a more favorable alternative. These results indicated that cis-Sesquisabinene hydrate could be one of the potential ligands for the treatment of inflammatory conditions. The druggability of the suggested compounds is confirmed by the in-silico ADMET study. This work will later serve as a foundation for experimental investigations conducted both in vitro and in vivo to confirm the anti-inflammatory capabilities of the same.

Supplementary information: The online version of this article (10.1007/s40203-025-00537-9) contains supplementary material, which is available to authorized users.