Virtual screening and bioassay study of novel inhibitors for bovine viral diarrhea virus RNA- dependent RNA polymerase

JUAN JOSÉ CASAL; ELIANA F. CASTRO ; LEAL, EMILSE S.; BOLLINI, MARIELA

Capital Federal

Simposio; Simposio Fronteras en Biociencia 2; 2016

Instituto de Investigación en Biomedicina de Buenos Aires ? CONICET ? Instituto Partner de la Sociead Max Planck (IBioBA-MPSP)

Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. Pestiviruses, including BVDV, border disease virus, and classical swine fever virus, are important animal pathogens. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses within the livestock industry each year. The global prevalence of persistent BVDV infection and the lack of a highly effective antiviral therapy have spurred intensive efforts to discover and develop novel anti-BVDV therapy in the pharmaceutical industry.BVDV NS5B RNA-dependent RNA polymerase (RdRp), the centerpiece for viral replication, constitutes a valid target for drug discovery. These progresses hold a considerable promise to the development of novel, specific and highly effective therapeutics to achieve sustained response and ultimately the eradication of BVDV infection. Viral RNA-dependent RNA polymerases differ from DNA-dependent RNA polymerases, DNA-dependent DNA polymerases, and reverse transcriptases in that RdRps contain "fingertips" consisting of several polypeptide strands in the fingers domain interacting with the thumb domain.Viral polymerase non-nucleoside inhibitors usually bind to allosteric sites in the polymerase and either ?lock? the enzyme into an inactive form or prevent conformational changes required to initiate and/or elongate a new RNA product.In this study, we have demonstrated that a combination of structure-based rational design, virtual screening, molecular dynamics and in vitro assays is an effective approach for the identification of a series of compounds that inhibited the growth of BVDV, and appeared to target a protein involved in viral RNA replication.