In silico development of a novel putative inhibitor of the 3C protease of Coxsackievirus B3 with a benzene sulfonamide skeleton

Abstract

Availability of X-ray crystal structure of 3C protease of several enteroviruses provided an opportunity for in silico drug design and development approach. Presented study is aimed at designing a novel compound targeting 3C protease of Coxsackievirus (CVB3), which is reported frequently to cause myocarditis in North America and Europe. A pthalimido-sulfonamide derivative (ZINC13799063) was identified through high-throughput virtual screening (HTVS) approach from the top HITs. A small library of phalimido-sulphonamides was enumerated to find a potential LEAD. Compound 17 from the library was found to inhibit CVB3 selectively in cell based antiviral assay at a concentration of EC50=1.0±0.1 µM with a selectivity index of >140. Molecular dynamics study was performed to investigate the selective inhibition of CVB3 over CVB4.

A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses

“…CVB3 WT (5 × 10 5 TCID 50 /mL) was incubated with 20 μM compound 17, 20 μM compound 15 (an inactive analogue) [22], or an equal volume of assay medium) at six different temperatures ranging from 37–52°C for 2 min, followed by rapid cooling to 4°C. Subsequently, the infectious virus load of the different samples was quantified by end-point titration.…”