2FLE

Structural analysis of asymmetric inhibitor bound to the HIV-1 Protease V82A mutant

Summary for 2FLE

• Entry DOI: 10.2210/pdb2fle/pdb
• Descriptor: pol protein, GLYCEROL, (2S,2'S)-N,N'-[(2S,3S,4S,5S)-1-CYCLOHEXYL-3,4-DIHYDROXY-6-PHENYLHEXANE-2,5-DIYL]BIS[3-METHYL-2-({[METHYL(PYRIDIN-2-YLMETHYL)AMINO]CARBONYL}AMINO)BUTANAMIDE], ... (4 entities in total)
• Functional Keywords: hiv-1 protease, inhibitor, resistance, induced fit, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22388.50

Authors

Clemente, J.C.,Robbins, A.,Dunn, B.M.,Sussman, F. (deposition date: 2006-01-05, release date: 2007-01-16, Last modification date: 2023-08-30)

Primary citation

Clemente, J.C.,Robbins, A.,Grana, P.,Paleo, M.R.,Correa, J.F.,Villaverde, M.C.,Sardina, F.J.,Govindasamy, L.,Agbandje-McKenna, M.,McKenna, R.,Dunn, B.M.,Sussman, F.
Design, synthesis, evaluation, and crystallographic-based structural studies of HIV-1 protease inhibitors with reduced response to the V82A mutation.
J.Med.Chem., 51:852-860, 2008

PubMed Abstract: In our quest for HIV-1 protease inhibitors that are not affected by the V82A resistance mutation, we have synthesized and tested a second generation set of C2-symmetric HIV-1 protease inhibitors that contain a cyclohexane group at P1 and/or P1'. The binding affinity results indicate that these compounds have an improved response to the appearance of the V82A mutation than the parent compound. The X-ray structure of one of these compounds with the V82A HIV-1 PR variant provides the structural rationale for the better resistance profile of these compounds. Moreover, scrutiny of the X-ray structure suggests that the ring of the Cha side chain might be in a boat rather than in the chair conformation, a result supported by molecular dynamics simulations.

PubMed: 18215016
DOI: 10.1021/jm701170f

Experimental method

X-RAY DIFFRACTION (1.9 Å)