X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease

• Published in: Bioorganic & medicinal chemistry Vol. 10; no. 8; pp. 2803 - 2806
• Main Authors: STOLL, Vincent, WENYING QIN, KEMPF, Dale, SHAM, Hing L, NORBECK, Daniel W, STEWART, Kent D, JAKOB, Clarissa, CHANG PARK, WALTER, K, SIMMER, R. L, HELFRICH, Rosalind, BUSSIERE, Dirk, KAO, J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.08.2002
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites - genetics; Biological and medical sciences; Crystallization; Crystallography, X-Ray; HIV Protease - chemistry; HIV Protease Inhibitors - chemistry; Humans; Hydrogen Bonding; Lopinavir; Medical sciences; Molecular Structure; Mutation; Pharmacology. Drug treatments; Protein Binding; Pyrimidinones - chemistry; HIV-1 virus; Enzyme; Nitrogen heterocycle; Peptidomimetic compound; Lopinavir; Active site; Retroviridae; Enzyme inhibitor; Lentivirus; Modeling; Biological activity; Virus; Peptidases; Molecular model; Hydrolases; Antiviral; Pyrimidine derivatives; Ureas; Human immunodeficiency virus; Secondary alcohol; Protease inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/s0968-0896(02)00051-2

The crystal structure of ABT-378 (lopinavir), bound to the active site of HIV-1 protease is described. A comparison with crystal structures of ritonavir, A-78791, and BILA-2450 shows some analogous features with previous reported compounds. A cyclic urea unit in the P(2) position of ABT-378 is novel and makes two bidentate hydrogen bonds with Asp 29 of HIV-1 protease. In addition, a previously unreported shift in the Gly 48 carbonyl position is observed. A discussion of the structural features responsible for its high potency against wild-type HIV protease is given along with an analysis of the effect of active site mutations on potency in in vitro assays.