In silico pharmacology最新文献

Drug-resistant Plasmodium falciparum has been on the rise, mainly due to point mutations in the pfDHFR or dihydrofolate reductase gene. This has heightened urgency to discover and develop new antimalarial drugs. This research utilized Pharmacophore Modeling, Virtual Screening, Molecular Docking and Molecular Dynamics Simulation techniques to identify potential pfDHFR inhibitors from virtual databases. Ligand-based pharmacophore hypothesis (H1) (r = 0.949, r² = 0.883) was formulated using a training set of 28 compounds that demonstrated pfDHFR inhibitory activity across four orders of magnitude. Additionally, a Structure-based Pharmacophore Hypothesis (P1) was derived from the ligand-binding site in the pfDHFR protein. The thoroughly validated hypotheses (H1 and P1) were then employed as 3D queries to screen compounds from the chemical database. These compounds were initially screened for drug-likeness and ADME/Tox properties before undergoing pharmacophore mapping. Pharmacophore mapping and docking analyses, followed by 200 ns molecular dynamics simulations using a mutant pfDHFR model, identified three promising lead candidates from the TCM database. The top compound, ZINC70454408, exhibited the highest H Bond energy of -14.204 kcal/mol and a predicted Ki of 0.04 µM, maintaining structural stability with an average RMSD of 2.1 Å throughout the simulation. Two additional compounds, ZINC04096650 and ZINC85631105, also exhibited strong binding energies (- 122.64 and - 118.92 kcal/mol, respectively) and low predicted Ki values (< 0.1 µM), with stable RMSD values ranging between 2.0 and 2.4 Å. These findings underscore ZINC70454408 as the most promising natural product-based pfDHFR inhibitor candidate and provide a compelling rationale for future experimental validation.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00533-z.

Rheumatoid arthritis (RA) is a systemic inflammatory condition that can lead to increased death rates, severe disability, and destructive joint damage. The prevalence of RA is the most frequent of all inflammatory diseases and is reported to affect 0.1-2.0% of the population worldwide. The incidence and disability-adjusted life years rates of RA in India have shown an increasing trend from 1990 to 2021. In the current investigation, a pharmacoinformatics approach was used to explore the potential synthetic derivative compounds of curcumin against unexplored hub genes associated with the therapeutics of RA in the Indian population. Such investigations could not only cut short the in-vitro and in-vivo experimental approaches. Herein, a GWAS of RA was conducted in a genetically distinct Indian population. CD4, STAT4, and CCR6 genes were identified and reconfirmed by a few previously reported GWAS findings, which revealed CCR6 as one of the key targets associated with RA. Lipinski's rule was used to determine the adsorption, distribution, metabolism, and excretion of ligands for drug suitability, and acute toxicity was also predicted. However, further docking analysis was carried out for curcumin and its nine derivatives against CCR6, STAT4, and CD4 human proteins compared with standards, i.e., Methotrexate and Hydroxychloroquine. Based on molecular docking, toxicity, and pharmacokinetics, the MD simulation study was observed for CCR6, STAT4, and CD4 with Methotrexate complex, Hydroxychloroquine complex, and pentagamavuton complex, respectively. This study revealed pentagamavuton as an active therapeutic that majorly inhibits the activity of the pivotal receptor CCR6, STAT4, and CD4 in humans.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00547-7.

Kalanchoe blossfeldiana, a medicinal succulent known for rich phytochemical diversity, hasn't been extensively explored for lipid-lowering potential. Given growing burden of hyperlipidemia and limitations of current therapies, novel natural alternatives with multi-target synergistic mechanisms are of increasing interest. This study aimed to investigate antihyperlipidemic activity of K. blossfeldiana leaf extracts and its bioactive compounds through multidisciplinary approach. Sequential extractions were performed using solvents of increasing polarity. Phytochemical estimation revealed that ethanolic cold extract obtained via ultrasonic-assisted cold extraction exhibited highest phenolic (102.46 ± 2.05 µg/mL) and flavonoid (86.88 ± 1.29 µg/mL) content, LC-MS/MS-QQQ analysis identified 61 phytocompounds, including kaempferol-3-O-rutinoside, kaempferol-3-O-glucuronide, quercetin-3,4'-di-O-glucoside, quercetin-3-O-rutinoside, and apigenin-7-O-glucoside. Ethanolic cold extract showed potent pancreatic lipase inhibition via fluorometric assay (IC₅₀ = 23.33 µg/mL) comparable to standard orlistat and significantly improved lipid profiles in cholesterol-fed female albino rats, reducing cholesterol, triglycerides, LDL-C, and VLDL-C while increasing HDL-C (P < 0.005) comparable to standard atorvastatin. Molecular docking revealed strong binding affinities, particularly for quercetin-3-O-rutinoside against HMG-CoA reductase (- 9.023 kcal/mol) and quercetin-3,4'-di-O-glucoside against pancreatic lipase-colipase (- 9.139 kcal/mol). Molecular Dynamic simulations over 100 ns confirmed stability of these complexes with minimal RMSD and RMSF fluctuations. In silico ADMET profiling indicated favorable pharmacokinetic and toxicity profiles for both compounds (LD₅₀ 5000 mg/kg). Multidisciplinary evidence supports the ethanolic cold extract of K.blossfeldiana as promising antihyperlipidemic agent. Quercetin-based derivatives were identified as key bioactives, meriting further investigation for isolation and development as lead compounds. Further pharmacokinetic, toxicity, and efficacy studies are necessary for clinical translation.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-026-00560-4.

Alternaria alternata is a common airborne fungus that can be found in both indoor and outdoor environments. It is a major allergen linked to respiratory diseases such as allergic rhinitis and asthma. It may also infect the skin, nails, or eyes. In addition, uncharacterized or hypothetical proteins are present but have not yet been identified or associated with specific protein sequences. Domains of undetermined activity refer to molecules with known, experimentally determined activity. Yet, the exact role or structural features of these proteins have not been identified. Many proteins encoded in A. alternata genome remain uncharacterized, including the hypothetical protein XP_018378625.1 containing the SRC1lrK2f domain, whose function is unknown. This research employed a comprehensive in-silico approach to predict its physicochemical features, structural properties, subcellular localization, and protein-protein interactions and 3D structure. The protein was found to be hydrophilic, with an instability index of 46.62 and isoelectric point value of 6.41 which indicates acidic nature. The in-silico analysis indicated that the protein is soluble, with its secondary structure mainly composed of a random coil suggesting structural flexibility. The analysis showed that the protein contains a cytoplasmic domain. Moreover, the protein-protein interactions were examined using STRING software, which showed that the SRC1lrK2f protein has a strong interaction with exodeoxyribonuclease 1, implying a possible role in DNA repair or genome maintenance. These findings provide the first functional insights into the SRC1lrK2f domain in A. alternata and may support the future development of pharmaceutical strategies for managing Alternaria-induced allergic and infectious diseases by advancing our understanding of the biological role of the SRC1lrK2f domain.

Carbapenemes are most powerful antibiotics available for the treatment of bacterial infections. However, bacteria have evolved the enzyme carbapenemase, specifically the New Delhi metallo-β-lactamase (NDM-1), hydrolyses broad spectrum of β-lactam antibiotics, including carbapenems, the last line of defense against infections, thus raising a significant global health issue. Hence, NDM-1 is a promising drug target against antibiotic resistance. A structure-based in silico approach employed to identify potential inhibitors of NDM-1. Virtual screening of 13,526 antibacterial compounds yielded ten candidates with the most favorable binding affinities (- 9.50 to - 8.07 kcal/mol), outperforming the reference ligand 7UOX-Lig (- 5.81 kcal/mol). Molecular dynamics simulations confirmed the stable binding of compounds 11,871, 12,801, 13,206, and 12,498, further supported by favorable MM/GBSA binding free energy values and consistent interaction profiles. The favorable thermodynamic profiles suggest that these compounds are promising NDM-1 inhibitors. They serve as potential leads for further optimization and experimental validation in developing novel therapeutics against NDM-1-mediated antibiotic resistance. Further in vitro and biochemical studies are warranted to confirm their efficacy and specificity, emphasizing the critical role of NDM-1 as a key target in combating β-lactam resistance.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00534-y.

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.