title: Inhibition of human immunodeficiency virus-1 protease by a C2-symmetric phosphinate. Synthesis and crystallographic analysis.
abstract: The human immunodeficiency virus type 1 (HIV-1) protease is a potential target of acquired immune deficiency syndrome (AIDS) therapy. A highly potent, perfectly symmetrical phosphinate inhibitor of this enzyme, SB204144, has been synthesized. It is a competitive inhibitor of HIV-1 protease, with an apparent inhibition constant of 2.8 nM at pH 6.0. The three-dimensional structure of SB204144 bound to the enzyme has been determined at 2.3-A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel F(o) magnitude to - Fc parallel/sigma magnitude of F(o)), of 0.178. The inhibitor is held in the enzyme active site by a set of hydrophobic and hydrophilic interactions, including an interaction between Arg8 and the center of the terminal benzene rings of the inhibitor. The phosphinate establishes a novel interaction with the two catalytic aspartates; each oxygen of the central phosphinic acid moiety interacts with a single oxygen of one aspartic acid, establishing a very short (2.2-2.4 A) oxygen-oxygen contact. As with the structures of penicillopepsin bound to phosphinate and phosphonate inhibitors [Fraser, M. E., Strynadka, N. C., Bartlett, P. A., Hanson, J. E., & James, M. N. (1992) Biochemistry 31, 5201-14], we interpret this short distance and the stereochemical environment of each pair of oxygens in terms of a hydrogen bond that has a symmetric single-well potential energy curve with the proton located midway between the two atoms.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Macromolecular Sciences, SmithKline Beecham, King of Prussia, Pennsylvania 19406.
authors.forename: S S
authors.initials: SS
authors.lastname: Abdel-Meguid
authors.forename: B
authors.initials: B
authors.lastname: Zhao
authors.forename: K H
authors.initials: KH
authors.lastname: Murthy
authors.forename: E
authors.initials: E
authors.lastname: Winborne
authors.forename: J K
authors.initials: JK
authors.lastname: Choi
authors.forename: R L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: M D
authors.initials: MD
authors.lastname: Minnich
authors.forename: J S
authors.initials: JS
authors.lastname: Culp
authors.forename: C
authors.initials: C
authors.lastname: Debouck
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis / Q000187:drug effects; D003460:Crystallization; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010721:Phosphinic Acids; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D013402:Sugar Alcohols / Q000737:chemistry; D014633:Valine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D014961:X-Ray Diffraction
chemical_list: D017320:HIV Protease Inhibitors; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D011994:Recombinant Proteins; D013402:Sugar Alcohols; C065300:A 74704; C082539:SB 204144; D016333:HIV Protease; D014633:Valine