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

• Published in: Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3387-3397
• 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: Carbamates - chemistry; Catalytic Domain; Crystallography, X-Ray; Drug Resistance, Viral; HIV Protease - chemistry; HIV Protease - genetics; HIV Protease Inhibitors - chemistry; HIV-1 - enzymology; Kinetics; Models, Molecular; Molecular Conformation; Mutation; Pyrrolidinones - chemistry; Sulfonamides - chemistry
• 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 Å were analyzed for complexes of 1 with the PR containing major drug resistant mutations, PRI47V, PRL76V, PRV82A, and PRN88D. 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 PRI47V and PRL76V and the altered charge of PRN88D are associated with significant local structural changes compared to the wild-type PRWT, while substitution of alanine in PRV82A 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 PRWT with similar inhibition constants in good agreement with the antiviral potency on multidrug resistant HIV-1.