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Fragment‐Based Screen against HIV Protease
Author(s) -
Perryman Alexander L.,
Zhang Qing,
Soutter Holly H.,
Rosenfeld Robin,
McRee Duncan E.,
Olson Arthur J.,
Elder John E.,
David Stout C.
Publication year - 2010
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00943.x
Subject(s) - chemistry , stereochemistry , hydrogen bond , salt bridge , moiety , binding site , molecule , fragment (logic) , protease , active site , crystallography , crystal structure , immunoglobulin fab fragments , peptide sequence , enzyme , biochemistry , complementarity determining region , mutant , organic chemistry , computer science , gene , programming language
We have employed a fragment‐based screen against wild‐type (NL4‐3) HIV protease (PR) using the Active Sight fragment library and X‐ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co‐crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3–1.3 Å resolution. Fragment binding induces a distinct conformation and specific crystal form of TL‐3 inhibited PR during co‐crystallization. One fragment, 2‐methylcyclohexanol, binds in the ‘exo site’ adjacent to the Gly16Gly17Gln18loop where the amide of Gly17is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys14and Leu63. Another fragment, indole‐6‐carboxylic acid, binds on the ‘outside/top of the flap’ via hydrophobic contacts with Trp42, Pro44, Met46, and Lys55, a hydrogen bond with Val56, and a salt‐bridge with Arg57. 2‐acetyl‐benzothiophene also binds at this site. This study is the first fragment‐based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor‐bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target.