Docking ligands into flexible and solvated macromolecules. 2. Development and application of fitted 1.5 to the virtual screening of potential HCV polymerase inhibitors.
HCV NS5B polymerase is a validated target for the treatment of hepatitis C, known to be one of the most challenging enzymes for docking programs. In order to improve the low accuracy of existing docking methods observed with this challenging enzyme, we have significantly modified and updated F itted 1.0, a recently reported docking program, into F itted 1.5. This enhanced version is now applicable to the virtual screening of compound libraries and includes new features such as filters and pharmacophore- or interaction-site-oriented docking. As a first validation, F itted 1.5 was applied to the testing set previously developed for F itted 1.0 and extended to include hepatitis C virus (HCV) polymerase inhibitors. This first validation showed an increased accuracy as well as an increase in speed. It also shows that the accuracy toward HCV polymerase is better than previously observed with other programs. Next, application of F itted 1.5 to the virtual screening of the Maybridge library seeded with known HCV polymerase inhibitors revealed its ability to recover most of these actives in the top 5% of the hit list. As a third validation, further biological assays uncovered HCV polymerase inhibition for selected Maybridge compounds ranked in the top of the hit list.
Corbeil
Christopher R
CR
Department of Chemistry, McGill University, 801 Sherbrooke St W, Montreal, QC, Canada H3A 2K6, and ViroChem Pharma Inc., 275 Armand-Frappier Blvd., Laval, QC, Canada H7V 4A7.
Englebienne
Pablo
P
Yannopoulos
Constantin G
CG
Chan
Laval
L
Das
Sanjoy K
SK
Bilimoria
Darius
D
L'heureux
Lucille
L
Moitessier
Nicolas
N
D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000201:enzymology*; D008024:Ligands; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D008024:Ligands; D012324:RNA-Dependent RNA Polymerase