Virology & Mycology
Open Access

Abstract

Analogues of 4-Hydroxypanduratin-A and Panduratin-A Serve as Potential Inhibitors against Ns2b/Ns3 Protease

Pramod Gware* and Geetika Gupta

The high impact of diseases caused by dengue viruses on global health is now reflected in an increased interest in the identification of drug targets and the rationale-based development of antiviral inhibitors which are suitable for a causative treatment of severe forms of dengue virus infections dengue haemorrhagic fever and dengue shock syndrome. A promising target for the design of specific inhibitors is the dengue virus NS3 serine protease which in the complex with the small activator protein NS2B-catalyses processing of the viral polyprotein at a number of sites in the nonstructural region. The NS3 protease is an indispensable component of the viral replication machinery and inhibition of this protein offers the prospect of eventually preventing dengue viruses from replication and maturation.

To this effect, several computational approaches were applied in this work. Initially molecular docking studies of reference ligands to the DEN3 NS2B/NS3 serine protease were carried out. These reference ligands consist of reported competitive inhibitors, 4-hydroxypanduratin A and panduratin A, screened from natural products database and 17 designed ligands GSP1, GSP2, GSP3, GSP4, GSP5, GSP6, GSP7, GSP8, GSP9, GSP10, GSP11, GSP12, GSP13, GSP14, GSP15, GSP16 and GSP17. In the designing of new lead inhibitors, the enzyme complexed to the reference ligands was minimized and their complexation energies (i.e., sum of interaction energy and binding energy) were computed. New compounds as potential dengue inhibitors were then designed by putting various substituents successively on the benzyl ring A of the reference molecule. These substituted benzyl compounds were then computed for their enzyme-ligand complexation energies. New enzyme-ligand complexes, exhibiting the lowest complexation energies and closest to the computed energy for the reference compounds, were then chosen. Thus, GSP6 is proposed as a potential inhibitor to the NS3/NS2B protease activities of DEN-3 with the lowest complexation energy of -92.4 kcal/mol. The design of drugs to treat dengue is at a very exciting crossroads, not only because scientific progress on DENV targets has been tremendous in the last five years, but also because the dengue problem is huge and is increasing, such that dengue might soon join the list of diseases with economically viable drug markets.

Published Date: 2022-02-04; Received Date: 2022-01-07