Two classes of HCV NS3 protease inhibitors (PIs) have beensuccessful in the clinic: reversibly-covalent and non-covalent inhibitors. Ourearly efforts in the discovery of novel non-covalent PIs were guided byintensive model building and later co-crystal structures. Since typicalnon-covalent PIs are often large, macrocyclic compounds with uniqueconformational restrictions, typical docking and scoring methods performedpoorly. However, a reasonable correlation between docking scores and experimental IC50 values for several hundred PIs were obtained with CDOCKER, a molecular dynamics and simulated-annealing-based docking program.Methods for further improving the docking and scoring performance were exploredusing pharmacophore filters and multiple scoring functions.

Computational challenges in lead optimization of HCV protease inhibition

239th National Meeting (2010)

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