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

Shovonlal Bhowmick; Siham A Alissa; Saikh Mohammad Wabaidur; Rupesh V Chikhale; Md Ataul Islam

doi:10.1002/jmr.2838

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

J Mol Recognit. 2020 Jul;33(7):e2838. doi: 10.1002/jmr.2838. Epub 2020 Feb 14.

Authors

Shovonlal Bhowmick¹, Siham A Alissa², Saikh Mohammad Wabaidur³, Rupesh V Chikhale⁴, Md Ataul Islam^{5

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Affiliations

¹ Department of Chemical Technology, University of Calcutta, Kolkata, India.
² Chemistry Department, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
³ Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia.
⁴ School of Pharmacy, University of East Anglia, Norwich, UK.
⁵ Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
⁶ School of Health Sciences, University of Kwazulu-Natal, Westville Campus, Durban, South Africa.
⁷ Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.

PMID: 32060998
DOI: 10.1002/jmr.2838

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.

Keywords: NS3-NS2B; dengue; molecular docking; molecular dynamics; virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dengue / drug therapy*
Molecular Docking Simulation
Molecular Dynamics Simulation
Protease Inhibitors / therapeutic use*
Viral Nonstructural Proteins / antagonists & inhibitors
Viral Nonstructural Proteins / metabolism

Substances

Protease Inhibitors
Viral Nonstructural Proteins