8FUI

HIV-1 wild type protease with GRL-02519A, with N-(2,5-dimethylphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine as P2-P3 group

Summary for 8FUI

• Entry DOI: 10.2210/pdb8fui/pdb
• Related: 2IEN 4ZIP 5UOV 5UPZ 6DV0 6DV4 8FUJ
• Descriptor: Protease, N-{(2S,3R)-4-[(4-aminobenzene-1-sulfonyl)(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl}-4-methyl-3-{[(4P)-4-(pyridin-3-yl)pyrimidin-2-yl]amino}benzamide, SODIUM ION, ... (8 entities in total)
• Functional Keywords: aspartic acid protease, hiv-1 protease, inhibitors, pyridylpyrimidine, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22592.17

Authors

Wang, Y.-F.,Wong-Sam, A.E.,Ghosh, A.K.,Weber, I.T. (deposition date: 2023-01-17, release date: 2023-05-24, Last modification date: 2024-05-22)

Primary citation

Ghosh, A.K.,Mishevich, J.L.,Kovela, S.,Shaktah, R.,Ghosh, A.K.,Johnson, M.,Wang, Y.F.,Wong-Sam, A.,Agniswamy, J.,Amano, M.,Takamatsu, Y.,Hattori, S.I.,Weber, I.T.,Mitsuya, H.
Exploration of imatinib and nilotinib-derived templates as the P2-Ligand for HIV-1 protease inhibitors: Design, synthesis, protein X-ray structural studies, and biological evaluation.
Eur.J.Med.Chem., 255:115385-115385, 2023

PubMed Abstract: Structure-based design, synthesis, X-ray structural studies, and biological evaluation of a new series of potent HIV-1 protease inhibitors are described. These inhibitors contain various pyridyl-pyrimidine, aryl thiazole or alkylthiazole derivatives as the P2 ligands in combination with darunavir-like hydroxyethylamine sulfonamide isosteres. These heterocyclic ligands are inherent to kinase inhibitor drugs, such as nilotinib and imatinib. These ligands are designed to make hydrogen bonding interactions with the backbone atoms in the S2 subsite of HIV-1 protease. Various benzoic acid derivatives have been synthesized and incorporation of these ligands provided potent inhibitors that exhibited subnanomolar level protease inhibitory activity and low nanomolar level antiviral activity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease were determined. These structures provided important ligand-binding site interactions for further optimization of this class of protease inhibitors.

PubMed: 37150084
DOI: 10.1016/j.ejmech.2023.115385

Experimental method

X-RAY DIFFRACTION (1.25 Å)