Rational design and virtual screening of novel inhibitors of HIV reverse transcriptase associated ribonuclease H based on a combined molecular modeling study.
A series of N-arylsulfonyl-indole-2-carboxamide derivatives have been identified as potent fructose-1,6-bisphosphatase (FBPase) inhibitors (FBPIs) with excellent selectivity for the potential therapy of type II diabetes mellitus. To explore the structure–activity relationships (SARs) and the mechanisms of action of these FBPIs, a systematic computational study was performed in the present study, including three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, pharmacophore modeling, molecular dynamics (MD), and virtual screening. The constructed 3D-QSAR models exhibited good predictive ability with reasonable parameters using comparative molecular field analysis (q2 = 0.709, R2 = 0.979, rpre2 = 0.932) and comparative molecular similarity indices analysis (q2 = 0.716, R2 = 0.978, rpre2 = 0.890). Twelve hit compounds were obtained by virtual screening using the best pharmacophore model in combination with molecular dockings. Three compounds with relatively higher docking scores and better ADME properties were then selected for further studies by docking and MD analyses. The docking results revealed that the amino acid residues Met18, Gly21, Gly26, Leu30, and Thr31 at the binding site were of great importance for the effective bindings of these FBPIs. The MD results indicated that the screened compounds VS01 and VS02 could bind with FBPase stably as its cognate ligand in dynamic conditions. This work identified several potential FBPIs by modeling studies and might provide important insights into developing novel FBPIs.
Capsid protein (Cp) plays an important role in the entire life cycle of Hepatitis B Virus (HBV) and is considered as a novel anti-HBV target. A series of novel sulfamoylbenzamide (SBA) derivatives have been recently identified as HBV capsid assembly modulators (CAMs) with EC 50 values at a low micromolar range. In this study, ligand-and receptor-based molecular simulations were performed to understand the structureactivity relationships (SARs) and the interaction mechanisms of these novel HBV CAMs. The constructed three-dimensional quantitative SAR (3D-QSAR) models exhibited good predictive abilities and well explained the SARs of these novel CAMs. Docking results suggested that HBV Cp TRP102 and THR128 might be key residues, which could form significant hydrogen bonds with these CAMs. Molecular dynamics (MD) results indicated that the most potent CAM could stably bind to the HBV Cp dimer or hexamer rather than the monomer, indicating that the inter-dimer interface might be important for SBA CAMs to stably bind with HBV Cp. Furthermore, five novel hit compounds (N1-5) as HBV CAMs were screened out by a comprehensive virtual screening. Compounds N1 and N2 were proved to bind well with the HBV Cp dimer and hexamer by MD simulations, and might have stronger interactions with the protein than the most potent SBA. These results might provide advantageous enlightenments for designing and developing novel HBV CAMs.
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