title: Potent antiviral HIV-1 protease inhibitor GRL-02031 adapts to the structures of drug resistant mutants with its P1'-pyrrolidinone ring.
abstract: GRL-02031 (1) is an HIV-1 protease (PR) inhibitor containing a novel P1' (R)-aminomethyl-2-pyrrolidinone group. Crystal structures at resolutions of 1.25-1.55 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR(I47V), PR(L76V), PR(V82A), and PR(N88D). Mutations of I47V and V82A alter residues in the inhibitor-binding site, while L76V and N88D are distal mutations having no direct contact with the inhibitor. Substitution of a smaller amino acid in PR(I47V) and PR(L76V) and the altered charge of PR(N88D) are associated with significant local structural changes compared to the wild-type PR(WT), while substitution of alanine in PR(V82A) increases the size of the S1' subsite. The P1' pyrrolidinone group of 1 accommodates to these local changes by assuming two different conformations. Overall, the conformation and interactions of 1 with PR mutants resemble those of PR(WT) with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.
authors.affiliation: Department of Biology, Molecular Basis of Disease Program, Georgia State University, P.O. Box 4010, Atlanta, Georgia 30302-4010, USA.
authors.forename: Yu-Chung E
authors.initials: YC
authors.lastname: Chang
authors.forename: XiaXia
authors.initials: X
authors.lastname: Yu
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Tie
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Sofiya
authors.initials: S
authors.lastname: Yashchuk
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Robert W
authors.initials: RW
authors.lastname: Harrison
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
mesh_terms: D002219:Carbamates / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry* / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology*; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011760:Pyrrolidinones / Q000737:chemistry*; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D002219:Carbamates; C540659:GRL 02031; D017320:HIV Protease Inhibitors; D011760:Pyrrolidinones; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1