In silico pharmacology最新文献

Alzheimer's disease, a major neurodegenerative disorder, is strongly linked to cholinergic dysfunction, making cholinesterase inhibition a key therapeutic strategy. Herein, the synthesis and in-silico studies of nitro-substituted Schiff base derivatives were studied as potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) targeting Alzheimer's disease. The three synthesized compounds (B1-B3) were obtained in good yields (68-73%). DFT results showed that the vibrational frequencies agreed with the experimental data, and B3 had the smallest HOMO-LUMO gap (6.026 eV) from frontier molecular orbital analysis, indicating higher chemical reactivity. NBO analysis showed it exhibits a strong donor-acceptor interaction with a stabilization energy of 34.80 kcal/mol. Molecular docking results (kcal/mol) showed that B1 (-7.09/-6.59), B2 (-5.30/-6.78), and B3 (-7.42/-6.35) exhibited stronger interactions with AChE and BChE respectively, than the reference drug rivastigmine (-6.66/-5.21). Molecular dynamics simulations showed that rivastigmine had the most favourable binding affinity for AChE, while the Schiff bases, B1-B3 outperformed Rivastigmine against BChE with B3 showing the strongest binding affinity (ΔG_bind = - 28.10 kcal/mol for AChE and - 26.31 kcal/mol for BChE) further confirming the result from DFT studies. Structural stability analyses revealed that AChE-B2 (RMSD = 1.384 Å, RoG = 22.817 Å) and BChE-B2 (RMSD = 1.619 Å, RoG = 23.211 Å) complexes were particularly stable, indicating that Schiff bases can form stable and energetically favorable interactions comparable to rivastigmine. Therefore, the study identifies B1 - B3 as promising dual cholinesterase inhibitors with favorable physicochemical properties, suggesting their potential as lead candidates for Alzheimer's disease therapy; however, further in-vitro and in-vivo investigations are essential to validate and confirm their efficacy and safety profiles.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00544-w.

Pathogenic fungi, particularly Candida albicans, have been escalating clinical problems, notably because of antifungal resistance and symptomatological comorbidity with COVID-19. This research aimed to find phytochemical inhibitors of ergosterol production, specifically targeting ERG6 (C-24 sterol methyltransferase), utilizing chemicals from the IMPPAT database. A total of 14,965 phytochemicals were computationally evaluated against AlphaFold-predicted ERG6 utilizing AutoDock Vina. Fifteen compounds exhibiting robust binding affinities (- 8.2 to - 9.2 kcal/mol) were found, from which four candidates were chosen based on advantageous ADMET profiles. The docking scores for the top four compounds targeting ERG6-Daturataturin A (- 8.8 kcal/mol), Disogluside (- 8.6), Tataramide B (- 8.4), and Floribundasaponin A (- 8.4)-exceeded those of previously identified ERG6 inhibitors D28 (- 8.0), Tomatidine (- 7.9), and H55 (- 6.4). The selected leads were further docked against other proteins associated with drug resistance and cell proliferation, specifically ERG1, ERG11, CLB2, CDR1, and CDR2. Among these, only ERG1 exhibited significant interactions, with Disogluside (- 9.3 kcal/mol), Tataramide B (- 9.9), and Floribundasaponin A (- 9.3) surpassing the reference inhibitor terbinafine (- 8.7 kcal/mol), except for Daturataturin A, which showed a comparable score of - 8.6 kcal/mol. Nevertheless, owing to steric conflicts inside the ERG1 binding sites, molecular dynamics (MD) simulations were conducted exclusively for ERG6-ligand complexes over duration of 100 ns. The RMSD values demonstrated commendable structural stability: Daturataturin A (~ 0.39 nm), Disogluside (~ 0.38 nm), Tataramide B (~ 0.27 nm), and Floribundasaponin A (~ 0.40 nm). Principal Component Analysis (PCA) validated consistent and significant movements for Daturataturin A and Floribundasaponin A, whereas Disogluside and Tataramide B exhibited increased flexibility. MM/PBSA analysis indicated robust binding free energies for Daturataturin A (- 42.26 kcal/mol), Floribundasaponin A (- 37.48 kcal/mol), and Disogluside (- 29.58 kcal/mol), however Tataramide B exhibited a detrimental + 9.81 kcal/mol. These results endorse the promise of phytochemical-derived antifungals and necessitate more experimental verification.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00480-9.

Research efforts for pancreatic cancer (PC) therapy has led to investigations of numerous therapeutic targets, yet there are still limited efficacy outcomes. In 2021, the annual PC cases of 508,533 resulted in mortality of 505,752 for both sexes according to GLOBOCAN. In order to address this burden, enhancer of zeste homolog 2 (EZH2); an epigenetic regulator implicated in various cancers, has been an attractive target, due to promising tumor-suppressive effects in both preclinical and clinical studies. This effect was observed from drugs that have strong affinity towards EZH2, but there is need to improve the structural moieties for better interaction towards this protein. In this study, we employed a structure-based drug discovery approach using CHEESE webserver for rapid ligand-based screening to identify and evaluate phytochemical derivatives for their potential to bind EZH2. Five phytochemicals, namely Moracin P, Naringenin 5-rhamnoside, Pinostrobin 5- glucoside, Phytocassane A, and Sakuranin with best performance against EZH2-PPARs from our previous study was used to generate top ten new derivatives each. The derivatives were subjected to molecular docking, pharmacokinetic, and toxicity predictions. The top-performing derivative interacting with EZH2 were further subjected to ADMET profiling with favorable pharmacokinetic, toxicity properties, and meeting key drug-likeness criteria. Molecular docking results revealed that several derivatives of Moracin P, Naringenin 5-rhamnoside, and Phytocassane A displayed higher predicted binding affinities (- 6.4 to - 8.2 Kcal/mol) compared to the parent template previously assessed for EZH2, engaging critical residues through hydrogen bonds and hydrophobic interactions. Molecular dynamic simulation (MDS) over 200 ns further confirmed the stability of selected protein-ligand complexes, with Moracin_P7 and Pinostrobin 5-glucoside_5 exhibiting high degrees flexibility within the first 100 ns, but remained stable for the last 100 ns, while contact analysis highlighted consistent interactions with the active site residues Gln653, Asp657, Asp664, Ser669, Asn673, Phe678, His711 and Tyr731. Conclusively, these findings provide evidence that CHEESE webserver is suitable to generate phytochemical derivatives that can be explored as feasible candidate in EZH2 inhibitory study and laying the groundwork for further in-vitro and in-vivo validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00536-w.

Bergenia ciliata a himalayan medicinal herb, which has been traditionally used due to its extensive pharmacological properties. Nevertheless, the possible anticancer application on the molecular level has not been fully explored. This experiment was developed to determine the phytochemicals of B. ciliata as natural inhibitors of the epidermal growth factor receptor (EGFR), which is a major target in most epithelial cancers. Phytochemical data on the IMPPAT and PubChem databases were collected. The compounds were using SwissADME and ProTox-II on drug-likeness, absorption, and toxicity. Then six candidates with Lipinski rule and pharmacokinetics conditions were docked to EGFR (PDB ID: 4HJO) with AutoDock vina. The binding affinities of cianidanol and Leucocianidol were the highest, - 8.8 kcal/mol and - 8.7 kcal/mol respectively, as compared to the reference drug erlotinib which has a binding affinity of - 8.3 kcal/Mol. There were several hydrogen bonds and hydrophobic interactions with such critical residues as Lys_721, Thr_766, Asp_831 and Phe_832.Simulations of 100 ns of molecular dynamics showed constant RMSD (0.10-0.20 nm), low fluctuations of residues, and small radius of gyration of all the complexes. MM/PBSA required interactions revealed that the stabilization was dominated by van der Waals forces and electrostatic repulsions with the total binding energies of - 51 kJ/mol, - 46 kJ/mol, and - 34 kJ/mol with cianidanol, leucocianidol, and erlotinib respectively. The studies suggests that EGFR is strongly bound by B. ciliata phytochemicals, and their biocompatible profiles are safer and more inclined to biocompatibility compared to the conventional inhibitor. These findings have indicated that these compounds can be useful lead scaffolds in the development of anticancer drugs in future as they have been shown to possess promising properties that would be further validated by studies conducted in in vitro and in vivo.

IDO1 has emerged as a compelling target for the development of novel therapies in diseases marked by immunosuppression, such as cancer. In recent years, growing evidence has also highlighted its involvement in non-immune signaling pathways, further enhancing its therapeutic potential. However, traditional drug design strategies focusing solely on targeting the active site of this enzyme exhibit limitations, leading to reduced selectivity and potential off-target effects. Consequently, alternative approaches, such as targeting allosteric pockets, are gaining attention driven by a growing understanding of protein dynamics, conformational flexibility, and their critical roles in regulating protein function. To address these challenges, we conducted an in-depth analysis of all available IDO1 crystal structures, which revealed an inactive conformation of the enzyme. Through this analysis, we identified an allosteric site unique to the inactive state of the protein, offering a novel opportunity to modulate its activity. Based on the population shift concept, we designed a ligand to selectively bind this druggable pocket, thereby stabilizing the inactive conformation of the enzyme. In vitro biological assays demonstrated that treatment with this compound effectively inhibits IDO1 activity, reduces tumor cell proliferation, and promotes dendritic cell maturation, as indicated by increased surface expression of CD86. Experimental validation of our conformationally driven inhibitor highlights the potential of a novel and innovative drug design strategy, introducing a new class of IDO1-targeting compounds. Our findings underscore the importance of understanding protein conformational dynamics and their influence on structure-function relationships as a foundation for the rational development of next-generation allosteric inhibitors.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00516-0.

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.