Identification of small molecule binding pocket for inhibition of crimean–congo hemorrhagic fever virus OTU protease

Abstract

Crimean–Congo hemorrhagic fever virus (CCHFV) is a deadly tick-borne virus with high mortality rates. Current antivirals lack specificity, making them susceptible to off-target effects and cytotoxicity. There is an utmost need for the identification of active compounds for anti-CCHFV therapies. Inhibition of CCHFV ovarian tumor (OTU) protease by small molecules is an exciting potential antiviral therapy. In this study, computational approaches based on residue homology, the binding coordinates of ligands, and correlation analysis with in vitro data identified the pocket of Y89–W99 as the inhibition site of CCHFV OTU protease. In silico screening of more than 600,000 compounds against this newly discovered pocket can identify potent inhibitors of CCHFV OTU protease. This novel set of compounds exhibits a common substructure and higher binding affinities. These findings distinguish the pocket of Y89–W99 as a pharmaceutical target for the optimization and identification of CCHFV OTU protease inhibitors that could serve as lead structures for discovering therapies against CCHFV.