Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Abstract

Dengue infection is the most common arthropod-borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi-step virtual screening effort was conceived to screen out the entire "screening library" of the Asinex database. Initially, through "Lipinski rule of five" filtration criterion almost 0.6 million compounds were collected and docked with NS3-NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the "Virtual Screening Workflow" (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as -high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM-GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3-NS2B protein based on the investigation of molecular interactions map and protein-ligand fingerprint analyses. Different pharmacokinetics and drug-likeness parameters were also checked, which favour the potentiality of selected molecules for being drug-like candidates. The molecular dynamics (MD) simulation analyses of protein-ligand complexes were explained that NS3-NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM-GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3-NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3-NS2B protein subjected to experimental validation.

Identification of potential anti-TMPRSS2 natural products through homology modelling, virtual screening and molecular dynamics simulation studies

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Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

“…As a result, a user defined binding affinity threshold score value of −7.00 kcal/mol was used for further screening criteria. More details of the employed ADV protocol can be found in our previous studies [ 48 , 49 ].…”

A short survey of dengue protease inhibitor development in the past 6 years (2015–2020) with an emphasis on similarities between DENV and SARS-CoV-2 proteases

“…Residues Lys74 and Leu76 were involved in hydrophobic interactions with the inhibitor, and the only π-cation interaction observed was between Lys74 and inhibitor. 89 6.3. Inhibitors identified through a rational approach 6.…”