title: 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 identified to complement this cleft. Subsequent experimental testing confirms inhibitory activity of this new class of inhibitor. This may be the first new inhibitor class for HIVp since dimerization inhibitors were introduced 17 years ago.
authors.affiliation: Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109-1065, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Damm
authors.forename: Peter M U
authors.initials: PM
authors.lastname: Ung
authors.forename: Jerome J
authors.initials: JJ
authors.lastname: Quintero
authors.forename: Jason E
authors.initials: JE
authors.lastname: Gestwicki
authors.forename: Heather A
authors.initials: HA
authors.lastname: Carlson
mesh_terms: D003198:Computer Simulation; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease