2QNQ

HIV-1 Protease in complex with a chloro decorated pyrrolidine-based inhibitor

Summary for 2QNQ

• Entry DOI: 10.2210/pdb2qnq/pdb
• Related: 2PQZ 2PWC 2PWR 2QNN 2QNP
• Descriptor: Gag-Pol polyprotein (Pr160Gag-Pol), CHLORIDE ION, N,N'-(3S,4S)-pyrrolidine-3,4-diylbis(N-benzyl-2-chlorobenzenesulfonamide), ... (4 entities in total)
• Functional Keywords: protein-ligand complex, aids, aspartyl protease, capsid maturation, core protein, cytoplasm, dna integration, dna recombination, dna-directed dna polymerase, endonuclease, hydrolase, lipoprotein, magnesium, membrane, metal-binding, multifunctional enzyme, myristate, nuclease, nucleotidyltransferase, phosphorylation, protease, rna-binding, rna-directed dna polymerase, transferase, viral nucleoprotein, virion, zinc, zinc-finger
• Biological source: Human immunodeficiency virus 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: 22344.48

Authors

Boettcher, J.,Blum, A.,Heine, A.,Diederich, W.E.,Klebe, G. (deposition date: 2007-07-19, release date: 2008-04-15, Last modification date: 2024-03-13)

Primary citation

Blum, A.,Bottcher, J.,Heine, A.,Klebe, G.,Diederich, W.E.
Structure-Guided Design of C2-Symmetric HIV-1 Protease Inhibitors Based on a Pyrrolidine Scaffold.
J.Med.Chem., 51:2078-2087, 2008

PubMed Abstract: Infections with the human immunodeficiency virus, which inevitably lead to the development of AIDS, are still among the most serious global health problems causing more than 2.5 million deaths per year. In the pathophysiological processes of this pandemic, HIV protease has proven to be an invaluable drug target because of its essential role in the virus' replication process. By use of pyrrolidine as core structure, symmetric 3,4-bis-N-alkylsulfonamides were designed and synthesized enantioselectively from D-(-)-tartaric acid as a new class of HIV protease inhibitors. Structure-guided design using the cocrystal structure of an initial lead as starting point resulted in a second series of inhibitors with improved affinity. The binding modes of four representatives were determined by X-ray crystallography to elucidate the underlying factors accounting for the SAR. With this information for further rational design, the combination of suitable side chains resulted in a final inhibitor showing a significantly improved affinity of K(i) = 74 nM.

PubMed: 18348517
DOI: 10.1021/jm701142s

Experimental method

X-RAY DIFFRACTION (2.3 Å)