Potent Antiviral HIV-1 Protease Inhibitor GRL-02031 Adapts to the Structures of Drug Resistant Mutants with Its P1;#8242;-Pyrrolidinone Ring

• Published in: Journal of medicinal chemistry 2012-11, Vol.55 ((7) ; 04, 2012)
• Main Authors: Chang, Yu-Chung E., Yu, XiaXia, Zhang, Ying, Tie, Yunfeng, Wang, Yuan-Fang, Yashchuk, Sofiya, Ghosh, Arun K., Harrison, Robert W., Weber, Irene T.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALANINES; AMINO ACIDS; BASIC BIOLOGICAL SCIENCES; CRYSTAL STRUCTURE; MUTANTS; MUTATIONS; PYRROLIDONES; RESIDUES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300072d

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 {angstrom} were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PR{sub I47V}, PR{sub L76V}, PR{sub V82A}, and PR{sub 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{sub I47V} and PR{sub L76V} and the altered charge of PR{sub N88D} are associated with significant local structural changes compared to the wild-type PR{sub WT}, while substitution of alanine in PR{sub 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{sub WT} with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.