In silico pharmacology最新文献

Non-synonymous single nucleotide polymorphisms (nsSNPs), also known as missense SNPs, can seriously affect an individual's vulnerability to numerous diseases, including cancer. In this study, we conducted a comprehensive in-silico analysis to examine the structural and functional implications of nsSNPs within the Folate Hydrolase 1(FOLH1) gene, which encodes the Prostate-Specific Membrane Antigen (PSMA). A total of 504 SNPs were retrieved, and after filtering, 15 pathogenic nsSNPs were identified using five different in-silico tools. Three of these SNPs-R255H (rs375565491), R255C (rs201789325), and G168E (rs267602926)-were consistently predicted to be pathogenic across all in-silico tools. MutPred2 was used to predict the structural and functional consequences of the identified mutations. The analysis revealed multiple alterations in the PSMA protein, including changes in helical conformations, glycosylation patterns, transmembrane properties, and solvent accessibility. Furthermore, I-Mutant 2.0 analysis demonstrated a decrease in protein stability for most nsSNPs, except for rs267602926 (G168E), which was predicted to increase stability. Conservation analysis using ConSurf revealed varying degrees of amino acid conservation, with R255H and R255C identified as highly conserved residues, indicating their potential functional and structural significance. Additionally, post-translational modification (PTM) analysis indicated that while phosphorylation and methylation sites remained unchanged, specific glycosylation sites were lost in two pathogenic mutant variants (R255H and R255C), potentially affecting PSMA function and adversely impacting prostate cancer. Our findings highlight the importance of in silico studies to investigate the structural and functional impacts of FOLH1 nsSNPs on the PSMA protein. Such in silico studies can deepen our understanding of the roles of nsSNPs in prostate cancer onset, progression, and drug resistance.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00319-3.

The primary objective of this study is to harness computer-aided drug repurposing (CADR) techniques to identify existing FDA-approved drugs that can potentially disrupt the assembly of the Hepatitis B Virus (HBV) core protein (HBcAg), an essential process in the virus's life cycle. By targeting this critical step, our study aims to expand the repertoire of therapeutic options for managing chronic Hepatitis B infection, a major global health challenge. Utilizing a combination of computational methods, including the CavityPlus server for ability to analyze druggable protein cavities and extract pharmacophore features and LigandScout for pharmacophore-based virtual screening of a vast library of FDA-approved drugs was conducted. Molecular dynamic simulation (MDS) was employed to evaluate the stability of HBcAg, complexed with Heteroaryldihydropyrimidine (HAP) and statins exhibiting particularly strong binding energies and conformational compatibility. Our approach focused on identifying pharmacophore features that align with known HBcAg inhibitors. The study identified several promising candidates, including Ciclopirox olamine, Voriconazole, Enasidenib, and statins, demonstrating potential interactions with HBc protein residues. Molecular docking further validated these interactions. The significance of these findings lies in their potential to offer new, effective therapeutic strategies for HBV treatment, particularly as alternatives to current therapies that often suffer from issues of viral resistance and adverse side effects. MDS analysis verified the robustness of HAP and statins by showing a high level of binding energies and compatibility with HBcAg. Our results provide a foundation for further experimental validation and underscore the utility of computer-aided drug repurposing as a rapid, cost-effective approach to drug discovery in antiviral research. This study contributes to our understanding of HBV biology and opens avenues for developing novel anti-HBV therapies based on repurposed drugs. The highlighted compound may also enhance the challenges of drug resistance when used as a combination therapy.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), still remains one of the leading causes of mortality worldwide. The elusive nature of this pathogen and its ability to develop drug resistance makes it a serious threat to global health. BCG, the only preventive vaccine for TB, has a limited efficacy and provides partial protection against the disease. A new effective recombinant vaccine capable of producing a stronger and more comprehensive immune response is required to address this global threat. In the present study, we adopted an in-silico approach to develop a multi-epitope vaccine by screening 198 "regulatory proteins" of Mtb H37Rv strain. Epitopes generated from these proteins were screened on the basis of antigenicity, cytokine profile, allergenicity, toxicity, conservancy and population coverage. Selected epitopes were docked with predominant MHC alleles that were used to develop a vaccine construct using suitable linkers and adjuvant. The construct was subjected to homology modelling, tertiary structure validation and refinement and was eventually docked with Toll-like receptor 2 receptor. Molecular dynamic simulation studies revealed stable interactions between the vaccine construct and TLR-2 receptor. The construct also displayed a high probability to elicit a protective immune response involving both humoral and cell-mediated components. In conclusion, the findings suggest that the constructed vaccine has the potential to induce a robust immune response against Mtb. However, further in-vitro and in-vivo studies are required to assess the safety, efficacy, and long-term protective effects of the vaccine construct.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00322-8.

Cancer prevention involves resisting cancer development at initial stages, retarding angiogenesis and initiating cancer cell apoptosis. Through the use of virtual screening, binding free energy calculations, and molecular dynamics simulations, we were able to identify compounds with potential anticancer activity."During the virtual screening process, compounds with promising drug-like properties were chosen using the Lipinski rule of five, and their binding affinities were evaluated by docking studies. In-silico activity of six different phytochemicals against established cancer specific proteins (NF-kB, p53, VEGF, BAX/BCl-2, TNF-alpha) were performed out of which p53, VEGF, BCl-2 has shown significant results. Sanguinarine has shown good docking score of -9.0 with VEGF and - 8.8 with Bcl-2 receptor and has been selected for molecular dynamics simulation. The results of Molecular Dynamics Simulations (MD) studies showed that RMSD and RMSF values of sanguinarine within an acceptable global minima (3-5.5 Å) for p53, VEGF, BAX/BCl-2. The computational models employed in this study produced important insights into the molecular mechanisms via which Sanguinarine prevents cancer by acting against p53, VEGF, and BCl-2 and by blocking the angiogenic, apoptotic, and proliferative pathways involved in the formation of cancer. The results suggest that the pharmacological activity of the selected phytomolecule (sanguinarine) is a promising avenue for cancer prevention.

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Malaria is a significant global health burden that affects the majority of people in the world. Nigeria still accounts for the highest percentage of the worldwide malaria burden, with 27% of estimated malaria cases and 31% of estimated deaths due to malaria in 2022. While antimalarial effects have been attributed to some active compounds from medicinal plants, no study has been conducted on Irvingia wombulu (IW). Therefore, this study aimed to evaluate the in silico antimalarial activity of some active compounds identified after gas chromatography/mass spectrometry (GC/MS) studies on Irvingia wombolu. The compounds were docked against the anti-malaria target Dihydrofolate Reductase-Thymidylate Synthase (DHFR-TS) of Plasmodium falciparum with PDB ID 3QGT and their pharmacokinetic properties were also predicted. This was followed by a molecular dynamics (MD) simulation of the protein in complex with the most promising IW compound. The GC-MS result revealed 44 phytoconstituents from IW. The Docking analysis revealed the following best binding energies (kcal/mol): alpha-tocopherol-beta-D-mannoside (-11.289), gamma-tocopherol (- 7.308), and linolenic acid (- 6.822). MD Simulation showed that the selected compound exhibited a stable conformation in the active site of the flexible protein. Pharmacokinetics analysis suggested that the compounds will be orally bio-available when administered. Therefore, these results indicate that these compounds can be considered for experimental validation and further development into antimalarial drugs.

Epigenetic dysfunction which has implicated disease conditions such as diabetes highlights the urgency for the discovery of novel therapeutic alternatives. The rising global incidences of diabetes and the limitations of existing treatments further exacerbate the quest for novel antidiabetic agents' discovery. This study leverages computational approaches to screen selected bioactive natural product phytoconstituents for their potential anti-diabetic properties. Utilizing pharmaceutical profiling, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) predictions, molecular docking, and molecular dynamics (MD) simulations, the drug-likeness and binding affinity of these natural compounds against human pancreatic amylase was investigated. Out of the total 24,316 ZINC compounds screened for their binding scores with amylase, ZINC85593620, ZINC85593668, and ZINC85490447 came top. The compounds had higher binding scores than the standards (acarbose and ranirestat) with ZINC85593620 having the highest docking score of - 12.162 kcal/mol and interacted with key amino acid residues such as TRP 59, ILE 148, and ASP 197. Further validation through MD simulations reveals that all the compounds showed minimal fluctuations relative to the standards indicating strong and stable binding interactions suggesting potential effective inhibition of the enzyme. ZINC85593620 and ZINC85593668 showed promising distribution and availability characteristics for amylase inhibition. Overall, the compounds displayed potential amylase inhibition which underscores their use as promising natural products in developing new antidiabetic drugs. Further experimental validations are recommended to offer a potential solution to the pressing need for safer and more effective antidiabetic therapies.

In COVID-19 patients, respiratory failure was reported due to damage to the respiratory centers of the brainstem. Molecular mimicry of three brainstem pre-Botzinger complex proteins (DAB1, AIFM and SURF1) was regarded as the underlying reason for respiratory failure and the autoimmune neurological sequelae. Of the three brainstem proteins mimicked by SARS CoV-2, corresponding sequences to two of the mimicry peptides were located in the N-protein of SARS CoV-2. N-protein is important for viral RNA synthesis and genome packaging. Here, we have used molecular modeling, docking and MD simulations to discern potential drugs which can inhibit molecular mimicry of DAB1 by SARS CoV-2 and also eliminate it by interfering in genome packaging. The binding site (drug target) for molecular docking was defined as the amino acid sequence extending from position 168-185 of the N-protein which was a SLiM region and also included the mimicry hexapeptide. Molecular docking after MD simulations was used to discern probable inhibitors of the drug-target from FDA-approved neurological drugs in the Broad Institute's Drug Repurposing Hub. Our results revealed that an anti-anxiety drug afobazole qualified the ADMET parameters, formed a stable complex with the drug-target and exhibited the highest binding energy (-88.21 kJ/mol). This suggests that afobazole can be repurposed against SARS CoV-2 for disrupting molecular mimicry of human DAB1 protein and also eliminate the etiopathological agent by interfering in viral genome packaging.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00316-6.

The global spread of monkeypox, caused by the double-stranded DNA monkeypox virus (MPXV), has underscored the urgent need for effective antiviral treatments. In this study, we aim to identify a potent inhibitor for MPXV DNA polymerase (DNAP), a critical enzyme in the virus replication process. Using a computational drug repurposing approach, we performed a virtual screening of 1615 FDA-approved drugs based on drug-likeness and molecular docking against DNAP. Among these, 1430 compounds met Lipinski's rule of five for drug-likeness, with Doxycycline emerging as the most promising competitive inhibitor, binding strongly to the DNAP active site with a binding affinity of - 9.3 kcal/mol. This interaction involved significant hydrogen bonds, electrostatic interactions, and hydrophobic contacts, with Doxycycline demonstrating a stronger affinity than established antivirals for smallpox, including Cidofovir, Brincidofovir, and Tecovirimat. Stability and flexibility analyses through a 200 ns molecular dynamics simulation and normal mode analysis confirmed the robustness of Doxycycline binding to DNAP. Overall, our results suggest Doxycycline as a promising candidate for monkeypox treatment, though additional experimental and clinical studies are needed to confirm its therapeutic potential and clinical utility.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00307-7.

Trypanosoma cruzi, the causative agent of Chagas disease, poses a life-threatening risk in both endemic and non-endemic regions. The parasite's survival depends on the production of sterols via the 14-α-demethylase (CYP51) metabolic pathway. Current treatments for Chagas disease are often associated with undesirable side effects and drug resistance. This study aimed to identify potential inhibitors of CYP51 using bioactive compounds derived from Tinospora cordifolia. A library of 122 compounds from T. cordifolia was screened against CYP51 using the Glide docking model in the Maestro-Schrodinger suite (2022). The top four leads were evaluated through e-pharmacophore modeling, pharmacokinetics (ADMET) analysis and molecular mechanics generalized Born surface area (MM-GBSA) calculations. The top four compounds exhibited superior binding affinity to CYP51 compared to the standard drug, benznidazole, with docking scores ranging from - 11.397 kcal/mol to - 9.539 kcal/mol. ADMET predictions suggested low cytotoxicity for these compounds. Among the leads, epicatechin and n-trans-caffeoyl tyramine showed the greatest stability, reduced flexibility, and compact conformations, making them promising candidates for further investigation. This study identifies potential inhibitors from T. cordifolia with high binding affinity and structural compatibility with CYP51. While these results are encouraging, further in vivo and in vitro studies are necessary to validate their efficacy as anti-Chagas agents.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00312-w.

Diabetes mellitus (DM) is one of the most common long-term metabolic illnesses with detrimental implications on health and 90-95% of DM cases worldwide are caused by type 2 diabetes (T2DM). The side effects of the existing medicines include vomiting, diarrhea, and serious damage to the kidneys, blood vessels, and nerves. Therefore, finding anti-diabetic medications without side effects is crucial. The main goal of this work is to find anti-diabetic inhibitors using in-silico evaluation techniques such as molecular docking, molecular dynamic simulation, principal component analysis, and drug probability analysis. The DPP-IV is one of numerous molecular targets implicated in the pathogenesis of DM and Diffractaic acid (DF) was docked into the active site of this enzyme to assess the inhibitory effect of DF. In addition, MD simulation and PCA were used to assess the stability of docked complex. Furthermore, the DF was then subjected to drug probability investigations. The binding affinity of the DF was - 40.2476 kcal/mol, which was comparable to the reference compound (- 43.0908 kcal/mol). Furthermore, the compound was in a stable structure, as demonstrated by MD simulation and PCA analysis. Based on drug probability tests, DF also demonstrated druggable qualities. The results of this investigation suggest that DF may function as a possible inhibitor against DM; nevertheless, more in vitro and in vivo investigations are required to validate the activity and other properties.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00321-9.