title: X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease.
abstract: 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.
authors.affiliation: Department of Structural Biology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Stoll
authors.forename: Wenying
authors.initials: W
authors.lastname: Qin
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Clarissa
authors.initials: C
authors.lastname: Jakob
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: K
authors.initials: K
authors.lastname: Walter
authors.forename: R L
authors.initials: RL
authors.lastname: Simmer
authors.forename: Rosalind
authors.initials: R
authors.lastname: Helfrich
authors.forename: Dirk
authors.initials: D
authors.lastname: Bussiere
authors.forename: J
authors.initials: J
authors.lastname: Kao
authors.forename: Dale
authors.initials: D
authors.lastname: Kempf
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Norbeck
mesh_terms: D001665:Binding Sites / Q000235:genetics; D003460:Crystallization; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D061466:Lopinavir; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011744:Pyrimidinones / Q000737:chemistry*
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease