1,720,984 research outputs found
Inhibition of Monkeypox Virus DNA Polymerase Using Moringa oleifera Phytochemicals: Computational Studies of Drug-Likeness, Molecular Docking, Molecular Dynamics Simulation and Density Functional Theory
No full textThe emergence of zoonotic monkeypox (MPX) disease, caused by the double-stranded DNA monkeypox virus (MPXV), has become a global threat. Due to unavailability of a specific small molecule drug for MPX, this study investigated Moringa oleifera phytochemicals to find potent and safe inhibitors of DNA Polymerase (DNA Pol), a poxvirus drug target due to its role in the viral life cycle. For that, 146 phytochemicals were screened through drug-likeness and molecular docking analyses. Among these, 136 compounds exhibited drug-like properties, with Gossypetin showing the highest binding affinity (- 7.8 kcal/mol), followed by Riboflavin (- 7.6 kcal/mol) and Ellagic acid (- 7.6 kcal/mol). In comparison, the control drugs Cidofovir and Brincidofovir displayed lower binding affinities, with binding energies of - 6.0 kcal/mol and - 5.1 kcal/mol, respectively. Hydrogen bonds, electrostatic and hydrophobic interactions were the main non-bond interactions between inhibitors and protein active site. The identified compounds were further evaluated using molecular dynamics simulation, density functional theory analysis and ADMET analysis. Molecular dynamics simulations conducted over 200 ns revealed that DNA Pol-Gossypetin complex was not stable, however, Riboflavin and Ellagic acid complexes showed excellent stability indicating them as better DNA Pol inhibitors. The density functional theory analysis exhibited the chemical reactivity of these inhibitor compounds. The ADMET analysis suggested that the top phytochemicals were safe and showed no toxicity. In conclusion, this study has identified Riboflavin and Ellagic acid as potential DNA Pol inhibitors to control MPXV. Further experimental assays and clinical trials are needed to confirm their activity against the disease
phytochemicals targeting EGFR: molecular docking, molecular dynamics simulation and density functional theory studies
No full textEpidermal growth factor receptor (EGFR) is a prominent target for anticancer therapy due to its role in activating several cell signaling cascades. Clinically approved EGFR inhibitors are reported to show treatment resistance and toxicity, this study, therefore, investigates Moringa oleifera phytochemicals to find potent and safe anti-EGFR compounds. For that, phytochemicals were screened based on drug-likeness and molecular docking analysis followed by molecular dynamics simulation, density functional theory analysis and ADMET analysis to identify the effective inhibitors of EGFR tyrosine kinase (EGFR-TK) domain. Known EGFR-TK inhibitors (1-4 generations) were used as control. Among 146 phytochemicals, 136 compounds showed drug-likeness, of which Delta 7-Avenasterol was the most potential EGFR-TK inhibitor with a binding energy of -9.2 kcal/mol followed by 24-Methylenecholesterol (-9.1 kcal/mol), Campesterol (-9.0 kcal/mol) and Ellagic acid (-9.0 kcal/mol). In comparison, the highest binding affinity from control drugs was displayed by Rociletinib (-9.0 kcal/mol). The molecular dynamics simulation (100 ns) exhibited the structural stability of native EGFR-TK and protein-inhibitor complexes. Further, MM/PBSA computed the binding free energies of protein complex with Delta 7-Avenasterol, 24-Methylenecholesterol, Campesterol and Ellagic acid as -154.559 ± 18.591 kJ/mol, -139.176 ± 19.236 kJ/mol, -136.212 ± 17.598 kJ/mol and -139.513 ± 23.832 kJ/mol, respectively. Non-polar interactions were the major contributors to these energies. The density functional theory analysis also established the stability of these inhibitor compounds. ADMET analysis depicted acceptable outcomes for all top phytochemicals without displaying any toxicity. In conclusion, this report has identified promising EGFR-TK inhibitors to treat several cancers that can be further investigated through laboratory and clinical tests
A computational study of the fold and stability of cytochrome c with implications for disease
Full text linkCytochrome c (Cyt-c), encoded by the CYCS gene, is crucial for electron transport, peroxidase activity, and apoptosis. Mutations in CYCS cause thrombocytopenia 4, a disorder with low platelet counts. We have, for instance, recently described six Italian families with five different heterozygous missense CYCS variants. These mutations likely enhance peroxidase and apoptotic activities, yet the mechanisms causing reduced platelet production and increased apoptosis are unclear. This study investigates clinically-related Cyt-c variants using an integrated bioinformatics approach. Our findings reveal that all variants are at evolutionarily conserved sites, potentially disrupting Cyt-c function and contributing to disease phenotypes. Specific variants are predicted to affect phosphorylation (T20I, V21G, Y49H), and ubiquitination (G42S, A52T, A52V, T103I). Molecular dynamics simulations (500 ns) revealed significant structural differences from the wild-type protein, with mutants showing reduced stability and increased unfolding and flexibility, particularly in the Ω-loops. These changes result in the displacement of the Ω-loops away from the heme iron, weakening critical hydrogen bonds and consequently opening the heme active site. This open conformation may enhance accessibility to small molecules such as H2O2, thereby promoting peroxidase activity, which may enhance apoptosis and likely impact megakaryopoiesis and platelet homeostasis in THC4
Repurposing doxycycline for the inhibition of monkeypox virus DNA polymerase: a comprehensive computational study
No full textThe 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
Repurposing FDA approved drugs against monkeypox virus DNA dependent RNA polymerase: virtual screening, normal mode analysis and molecular dynamics simulation studies
No full textZoonotic monkeypox disease, caused by the double-stranded DNA monkeypox virus, has become a global concern. Due to the absence of a specific small molecule drug for the disease, this report aims to identify potential inhibitor drugs for monkeypox. This study explores a drug repurposing strategy using virtual screening to evaluate 1615 FDA approved drugs against the monkeypox virus DNA dependent RNA polymerase subunit A6R. Normal mode analysis and molecular dynamics simulation assessed the flexibility and stability of the target protein in complex with the top screened drugs. The analysis identified Nilotinib (ZINC000006716957), Conivaptan (ZINC000012503187), and Ponatinib (ZINC000036701290) as the most potential RNA polymerase inhibitors with binding energies of - 7.5 kcal/mol. These drugs mainly established hydrogen bonds and hydrophobic interactions with the protein active sites, including LEU95, LEU90, PRO96, MET110, and VAL113, and residues nearby. Normal mode analysis and molecular dynamics simulation confirmed the stability of interactions between the top drugs and the protein. In conclusion, we have discovered promising drugs that can potentially control the monkeypox virus and should be further explored through experimental assays and clinical trials to assess their actual activity against the disease. The findings of this study could lay the foundation for screening repurposed compounds as possible antiviral treatments against various highly pathogenic viruses
In-silico prediction of TGF-β1 non-synonymous variants and their impact on binding affinity to Fresolimumab
No full textTGF-β1 is a potent immunoregulatory cytokine that plays diverse roles in development, bone healing, fibrosis, and cancer. However, characterizing TGF-β1 gene variants is challenging because the structural and functional consequences of these variants are still undetermined. In this study, we aimed to perform an in-silico analysis of TGF-β1 non-synonymous variants and their pathogenic effects on the TGF-β1 protein. A total of 10,252 TGF-β1 SNPs were collected from the NCBI dbSNP database and in-silico tools (SIFT, PROVEAN, Mutation Taster, ClinVar, PolyPhen-2, CScape, MutPred, and ConSurf) were used. The in-silico predicted potential variants were further investigated for their binding to the TGF-β1 targeting drug "Fresolimumab". Molecular docking was performed using HADDOCK and confirmed by PRODIGY and PDBsum. The in-silico analysis predicted four potential TGF-β1 nsSNPs: E47G in the LAP domain of the propeptide and I22T, L28F, and E35D in the mature TGF-β1 peptide. HADDOCK and molecular dynamics simulations revealed that the I22T and E35D variants have higher binding affinity for Fresolimumab as compared to the wild type and L28F variants. Molecular dynamics simulations (100 ns) and principal component analysis showed that TGF-β1 variants influenced the protein structure and caused variations in the internal dynamics of protein complexes with the antibody. Among them, the E35D variant significantly destabilized the TGF-β1 protein structure, resulting in rearrangement in the binding site and affecting the interactions with the Fresolimumab. This study identified four variants that can affect the TGF-β1 protein structure and result in functional consequences such as impaired response to Fresolimumab.Communicated by Ramaswamy H. Sarma
Berberine ameliorates the progression of primary sclerosing cholangitis by activating farnesoid X receptor
No full textPrimary sclerosing cholangitis (PSC) is a rare cholestatic disease characterized by biliary infiltration, hepatic fibrosis and bile duct destruction. To date, treatment options for PSC are very limited. Therefore, the current study is aimed to investigate the therapeutic potential of berberine (BBR) against PSC. The disease was induced by feeding the mice with 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC) for four weeks. The serum biochemistry and liver histology were analyzed. Furthermore, the expression of farnesoid X receptor (FXR) was also evaluated by real-time PCR. The results indicated that berberine prevents the progression of PSC by modulating the expression of FXR which ultimately regulates other genes (including Cyp7A1 and BSEP) thus maintaining bile acids homeostasis. Furthermore, the docking analysis showed that berberine interacts with the binding pocket of FXR to activate the protein thus acting as an FXR agonist. In conclusion, data indicate that berberine protects the liver from PSC-related injury. This effect might be due to the modulation of FXR activity
Ethyl 4-(1H-tetrazol-1-yl)benzoate derivatives as multi-target inhibitors of cancer migration via BTK, BRAF, and FAK modulation: in silico and in vitro studies
No full textMetastasis is the leading cause of cancer-related mortality, driven by complex processes such as cell migration and focal adhesion dynamics, which are regulated by key kinases including BTK, BRAF, and FAK. In this study, we designed, synthesized, and comprehensively evaluated a novel series of ethyl 4-(1H-tetrazol-1-yl)benzoate derivatives (Z1-Z7) as potential multi-target inhibitors of cancer metastasis. In silico analyses, including molecular docking and molecular dynamics simulations (MDs), identified compounds Z3 and Z4 as the most promising candidates, demonstrating strong and stable interactions with BTK, BRAF, and FAK. Density Functional Theory (DFT) calculations further supported these findings, revealing that Z3 and Z4 exhibited the lowest HOMO-LUMO energy gaps, indicating a high potential for charge transfer. Based on these results, Z3 was selected for in vitro validation, where it exhibited notable anticancer activity against A549 (IC50 = 2.522 μg/mL) and SKGT4 (IC50 = 1.576 μg/mL) cancer cell lines, while also displaying cytotoxicity toward normal Vero cells (IC50 = 2.758 μg/mL). Additionally, Z3 significantly inhibited cancer cell migration in wound healing assays, with effective concentrations of 0.5 μg/mL, 2.5 μg/mL, and 5 μg/mL for A549 cells, and 0.5 μg/mL, 1.6 μg/mL, and 3.2 μg/mL for SKGT4 cells. These findings suggest that ethyl 4-(1H-tetrazol-1-yl)benzoate derivatives, particularly Z3 and Z4, hold promise as multi-target therapeutic agents capable of modulating critical pathways involved in cancer migration and metastasis. With further optimization and validation, these compounds may contribute to the development of next-generation targeted therapies that address both tumor growth and the serious challenge of metastasis
A novel de novo GFAP variant causes a juvenile-onset Alexander disease with bilateral vocal cord paralysis
Full text linkAlexander disease (AxD), an autosomal dominant leukodystrophy, is caused by mutations in the GFAP, the gene encoding glial fibrillary acidic protein (GFAP). The disease, classified by age of onset into infantile, juvenile, and adult forms, is characterized by white matter degeneration and astrocytic inclusions called Rosenthal fibers. A patient underwent clinical, radiological, and molecular analyses to confirm a suspected diagnosis of AxD. The functional effect of the variant identified was tested using computational tools and in HeLa and astrocytoma cell lines. We report a case of juvenile AxD that clinically developed acute respiratory distress due to bilateral vocal cord paralysis. Brain and spinal cord MRI revealed the typical findings of the disease, including bulbospinal atrophy and T2-weighted hyperintensities in the frontal periventricular white matter. Molecular genetic testing identified a novel de novo c.713 T > G (p.I238S) variant of GFAP. In silico analyses revealed that the variant at evolutionarily conserved residue likely affects protein function. In vitro assays confirmed its pathogenic effect, showing that p.I238S protein expression significantly associates with aggregate formation in cellular models. Extending the clinical and molecular characterization of new cases of AxD is an important achievement to better characterize the disease
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