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- Background: Dental caries arise from polymicrobial biofilms and require interventions that address both local virulence and systemic burden. Methods: A curated set of 124 neem-derived phytochemicals was screened against Streptococcus mutans glucansucrase (3AIC) and Staphylococcus aureus DNA gyrase B (3U2D) using harmonized AutoDock Vina parameters. Ligand standardization and receptor preparation followed conventional protocols. Results: The most favorable docking scores reached −10.7 kcal·mol−1 for 3AIC and −8.9 kcal·mol−1 for 3U2D. Redocking produced pose RMSD values of 1.52 Å (3AIC) and 0.96 Å (3U2D). Per-receptor ADMET profiles for the six top-ranked compounds indicated median logP values of 4.93 (3AIC) and 4.52 (3U2D), median TPSA values of 80.3 and 62.9 Å2, median rotatable bonds of 2.5 and 1.0, and median QED values of 0.41 and 0.76, respectively. Conclusions: An integrated, dual-target screen prioritized neem constituents with plausible local anti-cariogenic activity and physicochemical features compatible with systemic disposition. These in silico findings motivate targeted experimental validation.
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- The development of clinically actionable pharmaceuticals against coronavirus disease (COVID-19); an infectious disease caused by the SARS-CoV-2 virus is very important for ending the pandemic. Coronavirus spike glyco protein (GP)-Receptor Binding Domain (RBD) and its interaction with host receptor angiotensin converting enzyme 2 (ACE2) is one of the most structurally understood but therapeutically untapped aspect of COVID-19 pathogenesis. Binding interface based on previous x-ray structure of RBD/ACE2 were virtually screened to identify fragments with high-binding score from 12,000 chemical building blocks. The hit compound was sub jected to fingerprint-based similarity search to identify compounds within the FDA-approved drug library con taining the same core scaffold. Identified compounds were then re-docked into of RBD/ACE2. The best ranked compound was validated for RBD/ACE2 inhibition using commercial kit. Molecular dynamics simulation was conducted to provide further insight into the mechanism of inhibition. From the original 12000 chemical building blocks, benzimidazole (BAZ) scaffold was identified. Fingerprint-based similarity search of the FDA- approved drug library for BAZ-containing compounds identified 12 drugs with the benzimidazole-like sub structure. When these compounds were re—docked into GP/ACE2 interface, the consensus docking identified bazedoxifene as the hit. In vitro RBD/ACE2 inhibition kinetics showed micromolar IC50 value (1.237 μM) in the presence of bazedoxifene. Molecular dynamics simulation of RBD/ACE2 in the presence BAZ resulted in loss of contact and specific hydrogen-bond interaction required for RBD/ACE2 stability. Taken together, these findings identified benzimidazole scaffold as a building block for developing novel RBD/ACE2 complex inhibitor and provided mechanistic basis for the use of bazedoxifene as a repurposable drug for the treatment of COVID-19 acting at RBD/ACE2 interface.
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- The high mutation rate of SARS-CoV-2 genomic RNA has made COVID-19 more difficult to eradicate using currently available interventions. Hence, newer pharmaceutical strategies must be developed, especially those generally complementary and alternative medicines. In the current study, stem bark of Bridelia ferruginea Benth is presented as plausible source of ethno-pharmaceuticals actionable against key SARS-CoV-2 life cycle-dependent enzymes based on in vitro inhibition studies, LC-ESI-MS characterization and molecular docking studies. Bridelia ferruginea stem bark extracted with 1 % HCL-acidified water, water, butanol, chloroform, ethyl-acetate, and petroleum ether and assayed for in vitro inhibition of SARS-COV-2-gp/human ACE2 interaction. The lowest and the highest IC50 value were recorded for ethyl-acetate (3.550 mg/L) and chloroform (413.4 mg/L) extracts respectively. When the ethyl-acetate extract was tested for SARS-COV-2 protease inhibition in vitro, papain-like protease (PL-pro, IC50=1.981 mg/L) presented as the better target in comparison to the main protease (3CL-pro, IC50=10.13 mg/L). LC/MS analysis identified corilagin and Gallocatechin-[4-O-7]-epigallocatechin as the active principles whilst molecular docking revealed the plausible poses of the compounds within the binding pockets of SARS-COV-2-glycoprotien receptor binding pocket, 3CL-pro and PL-pro. Taken together, these findings identified Bridelia ferruginea stem bark as a plausible source of anti-SARS-COV-2 phytochemicals and propose that corilagin may play important role in this activity.
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