2Q55

Crystal structure of KK44 bound to HIV-1 protease

Summary for 2Q55

• Entry DOI: 10.2210/pdb2q55/pdb
• Related: 2q54
• Descriptor: Protease, PHOSPHATE ION, (5S)-N-[(1S,2S,4S)-1-BENZYL-2-HYDROXY-4-{[(2S)-3-METHYL-2-(2-OXOTETRAHYDROPYRIMIDIN-1(2H)-YL)BUTANOYL]AMINO}-5-PHENYLPENTYL]-2-OXO-3-PHENYL-1,3-OXAZOLIDINE-5-CARBOXAMIDE, ... (4 entities in total)
• Functional Keywords: drug design, hiv-1 protease, protease inhibitor, hydrolase
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22477.31

Authors

Schiffer, C.A.,Nalam, M.N.L. (deposition date: 2007-05-31, release date: 2007-09-04, Last modification date: 2024-03-13)

Primary citation

Reddy, G.S.,Ali, A.,Nalam, M.N.,Anjum, S.G.,Cao, H.,Nathans, R.S.,Schiffer, C.A.,Rana, T.M.
Design and Synthesis of HIV-1 Protease Inhibitors Incorporating Oxazolidinones as P2/P2' Ligands in Pseudosymmetric Dipeptide Isosteres.
J.Med.Chem., 50:4316-4328, 2007

PubMed Abstract: A series of novel HIV-1 protease inhibitors based on two pseudosymmetric dipeptide isosteres have been synthesized and evaluated. The inhibitors were designed by incorporating N-phenyloxazolidinone-5-carboxamides into the hydroxyethylene and (hydroxyethyl)hydrazine dipeptide isosteres as P2 and P2' ligands. Compounds with (S)-phenyloxazolidinones attached at a position proximal to the central hydroxyl group showed low nM inhibitory activities against wild-type HIV-1 protease. Selected compounds were further evaluated for their inhibitory activities against a panel of multidrug-resistant protease variants and for their antiviral potencies in MT-4 cells. The crystal structures of lopinavir (LPV) and two new inhibitors containing phenyloxazolidinone-based ligands in complex with wild-type HIV-1 protease have been determined. A comparison of the inhibitor-protease structures with the LPV-protease structure provides valuable insight into the binding mode of the new inhibitors to the protease enzyme. Based on the crystal structures and knowledge of structure-activity relationships, new inhibitors can be designed with enhanced enzyme inhibitory and antiviral potencies.

PubMed: 17696512
DOI: 10.1021/jm070284z

Experimental method

X-RAY DIFFRACTION (1.9 Å)