Novel P2 Tris-tetrahydrofuran Group in Antiviral Compound 1 (GRL-0519) Fills the S2 Binding Pocket of Selected Mutants of HIV-1 Protease

详细信息    查看全文

• 作者：Hongmei Zhang ; Yuan-Fang Wang ; Chen-Hsiang Shen ; Johnson Agniswamy ; Kalapala Venkateswara Rao ; Chun-Xiao Xu ; Arun K. Ghosh ; Robert W. Harrison ; Irene T. Weber
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：February 14, 2013
• 年：2013
• 卷：56
• 期：3
• 页码：1074-1083
• 全文大小：540K
• 年卷期：v.56,no.3(February 14, 2013)
• ISSN：1520-4804

文摘

GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PR_R8Q, PR_D30N, PR_I50V, PR_I54M, and PR_V82A were analyzed in relation to kinetic data. The smaller valine side chain in PR_I50V eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PR_D30N showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6鈥?-fold lower inhibition. Gln8 in PR_R8Q replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.