Molecular Dynamics and MM/PBSA studies on thiosemicarbazones as inhibitors of BVDV RdRp

M. C. SORAIRES SANTACRUZ, M. FABIANI, E. F. CASTRO, L. V. CAVALLARO, L. M. FINKIELSZTEIN

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

In the search for new compounds with antiviral activity, we have found two thiosemicarbazones (2 and 15) that inhibit the replication of bovine viral diarrhea virus (BVDV). A cross-resistance assay against the BVDV RNA-dependent RNA polymerase (RdRp) wt and the N264D, A392E mutant indicated that compound 15 lost their inhibitory activity meanwhile the activity of compound 2 was maintained upon mutations.In this regard, we carried out molecular dynamics simulation and binding free energy calculations via MM/PBSA method to complement the experimental data of cross-resistance assays and to provide insights into the probable mode of action of compounds 2 and 15. The values of binding energies for compound 15 were in good agreement with the cross-resistance assay and prove that 15 is highly likely to act as a non-nucleoside inhibitor of the BVDV RdRp. In the case of compound 2, results suggest a different binding site or target.