4DJQ

Crystal Structure of wild-type HIV-1 Protease in Complex with MKP86

Summary for 4DJQ

• Entry DOI: 10.2210/pdb4djq/pdb
• Related: 4DJO 4DJP 4DJR
• Descriptor: Pol polyprotein, 2-(2-oxoimidazolidin-1-yl)ethyl [(2S,3R)-3-hydroxy-4-{[(4-methoxyphenyl)sulfonyl][(2S)-2-methylbutyl]amino}-1-phenylbutan-2-yl]carbamate, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: hiv-1 protease, drug resistance, drug design, protease inhibitors, aids, aspartyl protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22398.23

Authors

Schiffer, C.A.,Nalam, M.N.L. (deposition date: 2012-02-02, release date: 2012-08-01, Last modification date: 2024-02-28)

Primary citation

Parai, M.K.,Huggins, D.J.,Cao, H.,Nalam, M.N.,Ali, A.,Schiffer, C.A.,Tidor, B.,Rana, T.M.
Design, synthesis, and biological and structural evaluations of novel HIV-1 protease inhibitors to combat drug resistance.
J.Med.Chem., 55:6328-6341, 2012

PubMed Abstract: A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with K(i) values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies.

PubMed: 22708897
DOI: 10.1021/jm300238h

Experimental method

X-RAY DIFFRACTION (1.4 Å)