Repurposing of FDA-Approved Drugs for the Discovery of Inhibitors of Dengue Virus NS2B-NS3 Protease by Docking, Consensus Scoring, and Molecular Dynamics Simulations

Abstract

Dengue viruses (DENV) are transmitted by mosquitoes and infect ∼50 million people annually with an additional 2.5 billion people at risk living in tropical areas. However, there are no approved vaccines or antiviral therapies to combat the disease. DENV genome is translates into a single polyprotein comprising 3 structural and 7 non-structural (NS) proteins. The polyprotein precursor is cleaved by both host proteases and the two-component virus protease NS2B-NS3. Thus, this protease is considered as a promising target for antiviral design. In order to identify novel inhibitors of the DENV NS2B-NS3 protease we focused our strategy on the allosteric inhibitors capable of targeting the NS2B-NS3 interaction rather than the NS3 active site. The computational protocol was performed for 7,240- FDA-approved drugs retrieved from the ZINC database. We firstly implement a structure-based virtual screening to identify a preliminary set of inhibitors against the catalytic domain in active form of DENV NS2B-NS3 by docking analysis. The preliminary set inhibitors was then used to perform a consensus scoring of docking poses, based on scoring functions from the DrugScore and Xscore packages. Six docked poses were ranked among the top 50 compounds according to consensus scoring and were used to molecular dynamics (MD) simulation and free-energy calculation. Three compounds belonging to the piperazine derivatives family were finally proposed as potential inhibitors for DENV NS2B-NS3. These compounds target the allosteric-binding site of protease so that compound binding produces a conformational change able to affect the interaction among the protease and peptide substrates. The computational drug discovery strategy employed in our study could be applied for the identification of inhibitors of other flaviviral proteases.