4A6C

Stereoselective Synthesis, X-ray Analysis, and Biological Evaluation of a New Class of Lactam Based HIV-1 Protease Inhibitors

Summary for 4A6C

• Entry DOI: 10.2210/pdb4a6c/pdb
• Related: 1GNO 1WBK 1WBM 1ZPA 2CEJ 2CEM 4A4Q
• Descriptor: POL PROTEIN, METHYL ((S)-1-(2-(3-((3S,4S)-3-BENZYL-4-HYDROXY-1-((1S,2R)-2-HYDROXY-2,3-DIHYDRO-1H-INDEN-1-YL)-2-OXOPYRROLIDIN-3-YL)PROPYL)-2-(4-(PYRIDIN-4-YL)BENZYL)HYDRAZINYL)-3,3-DIMETHYL-1-OXOBUTAN-2-YL)CARBAMATE (3 entities in total)
• Functional Keywords: hydrolase, gamma-butyrol-lactam
• Biological source: HUMAN IMMUNODEFICIENCY VIRUS
• Total number of polymer chains: 2
• Total formula weight: 22285.21

Authors

Wu, X.,Ohrngren, P.,Joshi, A.A.,Trejos, A.,Persson, M.,Unge, J.,Arvela, R.K.,Wallberg, H.,Vrang, L.,Rosenquist, A.,Samuelsson, B.B.,Unge, J.,Larhed, M. (deposition date: 2011-11-01, release date: 2012-05-09, Last modification date: 2024-05-01)

Primary citation

Wu, X.,Ohrngren, P.,Joshi, A.A.,Trejos, A.,Persson, M.,Arvela, R.K.,Wallberg, H.,Vrang, L.,Rosenquist, A.,Samuelsson, B.B.,Unge, J.,Larhed, M.
Synthesis, X-Ray Analysis, and Biological Evaluation of a New Class of Stereopure Lactam-Based HIV-1 Protease Inhibitors.
J.Med.Chem., 55:2724-, 2012

PubMed Abstract: In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 μM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer).

PubMed: 22376008
DOI: 10.1021/JM201620T

Experimental method

X-RAY DIFFRACTION (1.5 Å)