Discovery of Novel Bovine Viral Diarrhea Inhibitors Using Structure-Based Virtual Screening on the Envelope Protein E2.
Bollini, M., Leal, E. S., Adler, N. S., Aucar, M. G., Fernandez, G. A., Pascual, M. J., Merwaiss, F., Alvarez, D. E. and Cavasotto, C. N.
Laboratorio de Quimica Medicinal, Centro de Investigaciones en Bionanociencias, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Ciudad de Buenos Aires, Argentina.
Laboratory of Computational Chemistry and Drug Design, Instituto de Investigacion en Biomedicina de Buenos Aires, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Partner Institute of the Max Planck Society, Ciudad de Buenos Aires, Argentina.
Instituto de Investigaciones Biotecnologicas, Universidad Nacional de San Martin, Consejo Nacional de Investigaciones Cientificas y Tecnicas, San Martin, Argentina.
Bovine viral diarrhea virus (BVDV) is a member of the genus Pestivirus within the family Flaviviridae. BVDV causes both acute and persistent infections in cattle, leading to substantial financial losses to 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 therapies in the pharmaceutical industry. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention of viral infections. We performed prospective small-molecule high-throughput docking to identify molecules that likely bind to the region delimited by domains I and II of the envelope protein E2 of BVDV. Several structurally different compounds were purchased or synthesized, and assayed for antiviral activity against BVDV. Five of the selected compounds were active displaying IC50 values in the low- to mid-micromolar range. For these compounds, their possible binding determinants were characterized by molecular dynamics simulations. A common pattern of interactions between active molecules and aminoacid residues in the binding site in E2 was observed. These findings could offer a better understanding of the interaction of BVDV E2 with these inhibitors, as well as benefit the discovery of novel and more potent BVDV antivirals.
Front Chem 6: 79 (2018)