A poke in the eye: inhibiting HIV-1 protease through its flap-recognition pocket.

ABSTRACT: A novel mechanism of inhibiting HIV-1 protease (HIVp) is presented. Using computational solvent mapping to identify complementary interactions and the Multiple Protein Structure method to incorporate protein flexibility, we generated a receptor-based pharmacophore model of the flexible flap region of the semiopen, apo state of HIVp. Complementary interactions were consistently observed at the base of the flap, only within a cleft with a specific structural role. In the closed, bound state of HIVp, each flap tip docks against the opposite monomer, occupying this cleft. This flap-recognition site is filled by the protein and cannot be identified using traditional approaches based on bound, closed structures. Virtual screening and dynamics simulations show how small molecules can be identifie

SUBMITTER: Damm KL 

PROVIDER: S-EPMC2859825 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature