On the role of theRconfiguration of the reaction-intermediate isostere in HIV-1 protease-inhibitor binding: X-ray structure at 2.0 Å resolution

Abstract

Peptidomimetic inhibitors of human immunodeficiency virus-1 protease are successful lead substances for the development of virostatic drugs against HIV as the causative agent of acquired immunodeficiency syndrome (AIDS). The hydroxyethylamine isostere of the proteolytic cleavage intermediate provides a suitable replacement for the peptide bond. A series of acyclic pseudopeptide inhibitors with the hydroxyethylamine isostere varying in chiral carbon configuration and P'2 residue type were structurally analysed by single-crystal X-ray crystallography. The compounds inhibit HIV protease with subnanomolar inhibition constants and block viral replication in tissue cultures. Here, the structure of such a complex with the R configuration of the isosteric group (PDB code 1zsf) is presented together with newly available synchrotron data for a complex with the S stereoisomer of the inhibitor (PDB code 1zsr). Comparison of the structure and binding with other complexes of HIV-1 protease and similar inhibitors contributes to the understanding of how these molecules bind to the wild-type form of this enzyme. The hydroxy group of the R stereoisomer interacts with one of the catalytic aspartic acids by a short hydrogen bond with rather extreme geometry. The change of configuration of the chiral carbon bearing the hydroxyl from S to R does not influence the inhibition efficiency in this case.

HIV-1 Protease Mutations and Inhibitor Modifications Monitored on a Series of Complexes. Structural Basis for the Effect of the A71V Mutation on the Active Site

“…Acronyms for complexes (e.g., WT−SQ) denote the protein type (wild-type, WT) and the inhibitor (SQ). Structures of complexes I8−SE and I8−SQ, newly determined within this study, are also compared with previously published structures WT−SE, WT−SQ, WT−OE, I8−OE, WT−QF34, and I8−QF34 . These structures form a unique series of similar and potent inhibitors with published structural data (for PDB codes and inhibition constants, see Table ).…”

New Active HIV‐1 Protease Inhibitors Derived from 3‐Hexanol: Conformation Study of the Free Inhibitors in Crystalline State and in Complex with the Enzyme

“…Based on experience in X‐ray structure determination of several HIV‐1 protease complexes with substrate‐analog inhibitors (41–43,61–65), we docked the 1 – 4 inhibitors into the binding site of HIV‐1 protease and optimized their geometry as described in . The X‐ray structures of 1 – 4 were used as input data for molecular modeling of their complexes with HIV‐1 protease.…”

“…The binding scheme of hydroxyethylene isostere inhibitors is well known [see for example several structures of complexes with HIV‐1 protease (1FQX, 1IIQ, 1LZQ, 1M0B, 1Z8C, 1ZBG, 1ZJ7, 1ZLF, 1ZPK, 1ZSF, 1ZSR) (41–43,62–65)]. A significant difference between conformation of those inhibitors and compounds 1 – 4 is in the antiparallel orientation of the amide groups at the opposite sides of the inhibitors’ main chains and in the non‐peptidic nature of inhibitors’ side chains.…”