3ST5

Crystal structure of wild-type HIV-1 protease with C3-Substituted Hexahydrocyclopentafuranyl Urethane as P2-Ligand, GRL-0489A

Summary for 3ST5

• Entry DOI: 10.2210/pdb3st5/pdb
• Related: 2HB3 2IEN 3DK1 3H5B
• Related PRD ID: PRD_000798
• Descriptor: Protease, CHLORIDE ION, (3R,3aR,5R,6aR)-3-hydroxyhexahydro-2H-cyclopenta[b]furan-5-yl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino}-1-phenylbutan-2-yl]carbamate, ... (4 entities in total)
• Functional Keywords: aspartic acid protease, hiv-1 protease inhibitor grl-0489a, c3-substituted hexahydrocyclopentafuranyl urethane as p2-ligands, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P03367
• Total number of polymer chains: 2
• Total formula weight: 22128.96

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2011-07-08, release date: 2011-08-17, Last modification date: 2023-09-13)

Primary citation

Ghosh, A.K.,Chapsal, B.D.,Parham, G.L.,Steffey, M.,Agniswamy, J.,Wang, Y.F.,Amano, M.,Weber, I.T.,Mitsuya, H.
Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Crystal Structure.
J.Med.Chem., 54:5890-5901, 2011

PubMed Abstract: We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions.

PubMed: 21800876
DOI: 10.1021/jm200649p

Experimental method

X-RAY DIFFRACTION (1.45 Å)