Synergistic experimental/computational studies on arylazoenamine derivatives that target the bovine viral diarrhea virus RNA-dependent RNA polymerase.
Starting from a series of arylazoenamine derivatives, shown to be selectively and potently active against the bovine viral diarrhea virus (BVDV), we developed a hierarchical combined experimental/molecular modeling strategy to explore the drug leads for the BVDV RNA-dependent RNA polymerase. Accordingly, BVDV mutants resistant to lead compounds in our series were isolated, and the mutant residues on the viral molecular target, the RNA-dependent RNA polymerase, were identified. Docking procedures upon previously identified pharmacophoric constraints and actual mutational data were carried out, and the binding affinity of all active compounds for the RdRp was estimated. Given the excellent agreement between in silico and in vitro data, this procedure is currently being employed in the design a new series of more selective and potent BVDV inhibitors.
Giliberti
Gabriele
G
Department of Biomedical Science and Technology, University of Cagliari, Cittadella Universitaria, 09042 Monserrato (Cagliari), Italy.
Ibba
Cristina
C
Marongiu
Esther
E
Loddo
Roberta
R
Tonelli
Michele
M
Boido
Vito
V
Laurini
Erik
E
Posocco
Paola
P
Fermeglia
Maurizio
M
Pricl
Sabrina
S
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001391:Azo Compounds / Q000737:chemistry* / Q000494:pharmacology*; D001912:Bovine Virus Diarrhea-Mucosal Disease / Q000188:drug therapy; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D015195:Drug Design; D024882:Drug Resistance, Viral; D030243:Hemorrhagic Syndrome, Bovine / Q000188:drug therapy; D006801:Humans; D008958:Models, Molecular; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D001391:Azo Compounds; D012324:RNA-Dependent RNA Polymerase