8F0F

HIV-1 wild type protease with GRL-110-19A, a chloroacetamide derivative based on Darunavir as P2' group

Summary for 8F0F

• Entry DOI: 10.2210/pdb8f0f/pdb
• Related: 2IEN 6U7O
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: aspartic acid protease, hiv-1 protease, darunavir, a chloroacetamide derivative inhibitor, antiviral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22326.94

Authors

Wang, Y.-F.,Agniswamy, J.,Ghosh, A.K.,Weber, I.T. (deposition date: 2022-11-02, release date: 2023-02-15, Last modification date: 2023-10-25)

Primary citation

Ghosh, A.K.,Shahabi, D.,Kipfmiller, M.,Ghosh, A.K.,Johnson, M.,Wang, Y.F.,Agniswamy, J.,Amano, M.,Weber, I.T.,Mitsuya, H.
Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.
Bioorg.Med.Chem.Lett., 83:129168-129168, 2023

PubMed Abstract: We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

PubMed: 36738797
DOI: 10.1016/j.bmcl.2023.129168

Experimental method

X-RAY DIFFRACTION (1.29 Å)