5JG1

HIV-1 wild Type protease with GRL-031-14A (a Adamantane P1-Ligand with tetrahydropyrano-tetrahydrofuran in P2 and isobutylamine in P1')

Summary for 5JG1

• Entry DOI: 10.2210/pdb5jg1/pdb
• Related: 2IEN 5JFP 5JFU
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: adamantane, hiv-1 protease inhibitor grl-031-14a, darunavir, multidrug-resistant, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22348.15

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2016-04-19, release date: 2016-09-21, Last modification date: 2023-09-27)

Primary citation

Ghosh, A.K.,Osswald, H.L.,Glauninger, K.,Agniswamy, J.,Wang, Y.F.,Hayashi, H.,Aoki, M.,Weber, I.T.,Mitsuya, H.
Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation.
J.Med.Chem., 59:6826-6837, 2016

PubMed Abstract: A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized, and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isosteres utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamantylmethyl in combination with P2 ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF, and THF-THP were examined. The S1' pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1' ligand and a bis-THF P2 ligand, proved to be the most potent of the series. The cLogP value of inhibitor 15d is improved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h, and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.

PubMed: 27389367
DOI: 10.1021/acs.jmedchem.6b00639

Experimental method

X-RAY DIFFRACTION (1.16 Å)