Pocket-to-Lead: Structure-Based De Novo Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template.

A novel strategy for lead identification that we have dubbed the "Pocket-to-Lead" strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized in silico . The designed compound 9 demonstrated weak but evident inhibitory activity (IC ₅₀ = 54 μM), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound 14 (IC ₅₀ = 0.0071 μM, EC ₅₀ = 0.86 μM), an almost 10,000-fold improvement in activity from 9 . The structure of the designed molecules proved to be novel with high synthetic feasibility, indicating the usefulness of this strategy to tackle tough targets with complex pharmacophore.