Pharmacophore modeling, resistant mutant isolation, docking, and MM-PBSA analysis: Combined experimental/computer-assisted approaches to identify new inhibitors of the bovine viral diarrhea virus (BVDV).
Starting from a series of our new 2-phenylbenzimidazole 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, a successful 3D pharmacophore model was developed, characterized by distinct chemical features that may be responsible for the activity of the inhibitors. BVDV mutants resistant to lead compounds in our series were then isolated, and the mutant residues on the viral molecular target, the RNA-dependent RNA-polymerase, were identified. Docking procedures upon pharmacophoric constraints and mutational data were carried out, and the binding affinity of all active compounds for the RdRp were 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.
Tonelli
Michele
M
Deparment of Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy.
Boido
Vito
V
Deparment of Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy.
Colla
Paolo La
P
Department of Biomedical Sciences and Technologies, University of Cagliari, Cittadella Universitaria, 09042 Monserrato (Cagliari), Italy.
Loddo
Roberta
R
Department of Biomedical Sciences and Technologies, University of Cagliari, Cittadella Universitaria, 09042 Monserrato (Cagliari), Italy.
Posocco
Paola
P
Molecular Simulation Engineering (MOSE) Laboratory, Department of Chemical, Environmental, and Raw Materials Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
Paneni
Maria Silvia
MS
Molecular Simulation Engineering (MOSE) Laboratory, Department of Chemical, Environmental, and Raw Materials Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
Fermeglia
Maurizio
M
Molecular Simulation Engineering (MOSE) Laboratory, Department of Chemical, Environmental, and Raw Materials Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
Pricl
Sabrina
S
Molecular Simulation Engineering (MOSE) Laboratory, Department of Chemical, Environmental, and Raw Materials Engineering, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D024882:Drug Resistance, Viral / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001562:Benzimidazoles; C117755:2-phenylbenzimidazole; D012324:RNA-Dependent RNA Polymerase