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A poke in the eye: Inhibiting HIV‐1 protease through its flap‐recognition pocket
Author(s) -
Damm Kelly L.,
Ung Peter M. U.,
Quintero Jerome J.,
Gestwicki Jason E.,
Carlson Heather A.
Publication year - 2008
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.20993
Subject(s) - pharmacophore , preprint , chemistry , human immunodeficiency virus (hiv) , flexibility (engineering) , protease , computational biology , monomer , combinatorial chemistry , stereochemistry , computer science , biochemistry , biology , virology , world wide web , enzyme , mathematics , statistics , organic chemistry , polymer
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. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 643–652, 2008. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com