Molecular Docking Studies of Thiosemicarbazones Derived from 1-indanones Against Bovine Viral Diarrhea Virus RNA-dependent RNA-polymerase

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

La Jolla, California

Congreso; 29th International Conference on Antiviral Research (ICAR); 2016

The Bovine Viral Diarrhea Virus (BVDV) RNA-dependent RNA-polymerase (RdRP) is an important target for drug discovery studies. Previously,we reported a series of thiosemicarbazones (TSCs) derived from 1-indanones as non-nucleoside inhibitors (NNIs) of BVDV RdRp (NS5B). Furthermore,we evaluated the activity of TSCs derived from N4-p-nitrophenyl-5,6-dimethoxy-1-indanone (1) and 6-nitro-1-indanone (2) against BVDV mutantsresistant to the TSC derived from 5,6-dimethoxy-1-indanone (lead compound) which carried N264D and A392E mutations in the NS5B. Hence, weperformed molecular docking studies in order to define the fundamental properties for the design of new drugs.Based on Lamarckian genetic algorithm, three TSCs were docked with wild-type and mutant RdRp using AutoDock4.0 software. The lead compounddocked in the mutant RdRp showed important differences respect to the wild-type. Hydrophobic interaction with the thiocarbonyl group, close contactwith the indane ring, and hydrogen bonds involving the thiosemicarbazone function are completely absent or considerably weaker in mutant.Compound 1 revealed some different interactions between wild-type and mutant RdRp, among them the absence of close contact with 5,6-dimethoxygroup in mutant. Finally, compound 2 showed no differences in ligand-protein interactions between wild-type and mutant RdRp, which suggests adifferent active site for this compound. The obtained results showed an excellent agreement between in silico and in vitro data.These studies revealed essential interactions between ligand-protein and helped in understanding the antiviral activity of TSCs at molecular level.Further molecular dynamics studies are being carried out for a deeper insight into the NNIs mechanism of inhibition of the BVDV RdRp