Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease.
Erickson J,
Neidhart DJ,
VanDrie J,
Kempf DJ,
Wang XC,
Norbeck DW,
Plattner JJ,
Rittenhouse JW,
Turon M,
Wideburg N, et al.
Department of Computer-Assisted Molecular Design, Abbott Laboratories, Abbott Park, IL 60064.
A two-fold (C2) symmetric inhibitor of the protease of human immunodeficiency virus type-1 (HIV-1) has been designed on the basis of the three-dimensional symmetry of the enzyme active site. The symmetric molecule inhibited both protease activity and acute HIV-1 infection in vitro, was at least 10,000-fold more potent against HIV-1 protease than against related enzymes, and appeared to be stable to degradative enzymes. The 2.8 angstrom crystal structure of the inhibitor-enzyme complex demonstrated that the inhibitor binds to the enzyme in a highly symmetric fashion.
PMID: 2200122 [PubMed - indexed for MEDLINE]