Pocket-to-Lead: Structure-BasedDe NovoDesign of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocketas a Template

摘要

A novel strategy for lead identification that we havedubbed the"Pocket-to-Lead"strategy is demonstrated using HIV-1protease as a model target. Sometimes, it is difficult to obtain hitcompounds because of the difficulties in satisfying the complexpharmacophoric features. In this study, a virtual fragment hit whichdoes not match all of the pharmacophore features but has keyinteractions and vectors that could grow into remainingpharmacophore features was optimizedin silico. The designedcompound9demonstrated weak but evident inhibitory activity(IC50=54 mu M), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound14(IC50= 0.0071 mu M, EC50= 0.86 mu M), an almost10,000-fold improvement in activity from9. The structure of the designed molecules proved to be novel with high syntheticfeasibility, indicating the usefulness of this strategy to tackle tough targets with complex pharmacophore.