3BGC

HIV-1 protease in complex with a benzyl decorated oligoamine

Summary for 3BGC

• Entry DOI: 10.2210/pdb3bgc/pdb
• Related: 3BGB
• Descriptor: Protease, N,N'-(iminodiethane-2,1-diyl)bis(4-amino-N-benzylbenzenesulfonamide), CHLORIDE ION, ... (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, nucleus, phosphoprotein, protease, rna-binding, rna-directed dna polymerase, transferase, viral nucleoprotein, virion, zinc, zinc-finger
• Biological source: Human immunodeficiency virus type 1 (Viruses)
• 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: 22272.18

Authors

Boettcher, J.,Blum, A.,Sammet, B.,Heine, A.,Diederich, W.E.,Klebe, G. (deposition date: 2007-11-26, release date: 2008-09-02, Last modification date: 2023-11-01)

Primary citation

Blum, A.,Sammet, B.,Luksch, T.,Heine, A.,Klebe, G.,Diederich, W.E.
Achiral oligoamines as versatile tool for the development of aspartic protease inhibitors
Bioorg.Med.Chem., 16:8574-8586, 2008

PubMed Abstract: Due to the important role that aspartic proteases play in many patho-physiological processes, they have intensively been targeted by modern drug development. However, up to now, only for two family members, renin and HIV protease, approved drugs are available. Inhibitor development, mostly guided by mimicking the natural peptide substrates, resulted in very potent inhibitors for several targets, but the pharmacokinetic properties of these compounds were often not optimal. Herein we report a novel approach for lead structure discovery of non-peptidic aspartic protease inhibitors using easily accessible achiral linear oligoamines as starting point. An initial library comprising 11 inhibitors was developed and screened against six selected aspartic proteases. Several hits could be identified, among them selective as well as rather promiscuous inhibitors. The design concept was confirmed by determination of the crystal structure of two derivatives in complex with the HIV-1 protease, and represents a promising basis for the further inhibitor development.

PubMed: 18760609
DOI: 10.1016/j.bmc.2008.08.012

Experimental method

X-RAY DIFFRACTION (1.8 Å)