Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Kiof 0.025 nM and antiviral IC50of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.

Ghosh, A.K., Brindisi, M., Nyalapatla, P.R., Takayama, J., Ella-Menye, J., Yashchuk, S., et al. (2017). Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. BIOORGANIC & MEDICINAL CHEMISTRY, 25(19), 5114-5127 [10.1016/j.bmc.2017.04.005].

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex

Brindisi, Margherita;
2017-01-01

Abstract

Based upon molecular insights from the X-ray structures of inhibitor-bound HIV-1 protease complexes, we have designed a series of isophthalamide-derived inhibitors incorporating substituted pyrrolidines, piperidines and thiazolidines as P2-P3 ligands for specific interactions in the S2-S3 extended site. Compound 4b has shown an enzyme Kiof 0.025 nM and antiviral IC50of 69 nM. An X-ray crystal structure of inhibitor 4b-HIV-1 protease complex was determined at 1.33 Å resolution. We have also determined X-ray structure of 3b-bound HIV-1 protease at 1.27 Å resolution. These structures revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.
Ghosh, A.K., Brindisi, M., Nyalapatla, P.R., Takayama, J., Ella-Menye, J., Yashchuk, S., et al. (2017). Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. BIOORGANIC & MEDICINAL CHEMISTRY, 25(19), 5114-5127 [10.1016/j.bmc.2017.04.005].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1030057