A CHECK ON RATIONAL DRUG DESIGN - CRYSTAL-STRUCTURE OF A COMPLEX OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE WITH A NOVEL GAMMA-TURN MIMETIC INHIBITOR

We have previously reported (Newlander et al., J. Med. Chem. 1993, 36, 2321-2331) the design of human immunodeficiency virus type 1 (HIV-1) protease inhibitors incorporating C-7 mimetics that lock three amino a cid residues of a peptide sequence into a gamma-turn. The design of on e such compound, SB203238, was based on X-ray structures of reduced am ide aspartyl protease inhibitors. It incorporates a gamma-turn mimetic in the P-2-P-1' position, where the carbonyl of the C-7 ring is repla ced with an sp(3) methylene group yielding a constrained reduced amide . It shows competitive inhibition with K-i = 430 nM at pH 6.0. The thr ee-dimensional structure of SB203238 bound to the active site of HIV-1 protease has been determined at 2.3 Angstrom resolution by X-ray diff raction and refined to a crystallographic R-factor (R = Sigma\F-o\ - \ F-c\/Sigma\F-o\, where F-o and F-c are the observed and calculated str ucture factor amplitudes, respectively) of 0.177. The inhibitor lies i n an extended conformation in the active site; however, because of the constrained geometry of the C-7 ring, it maintains fewer hydrogen bon ds with the protein than in most other HIV-1 protease-inhibitor comple xes. More importantly, the inhibitor binds to the enzyme differently t han predicted in its design, by binding with the P-2-P-1' alpha-carbon atoms shifted by approximately one-half a residue toward the N-termin us from their presumed positions. This study illustrates the importanc e of structural information in an approach to rational drug design.