3DK1

Wild Type HIV-1 Protease with potent Antiviral inhibitor GRL-0105A

Summary for 3DK1

• Entry DOI: 10.2210/pdb3dk1/pdb
• Related: 2HB3 2IEN 2Z4O 3DJK
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: hiv-1, wild type protease, protease inhibitor, hydrolase, aids, aspartyl protease, capsid maturation, capsid protein, cytoplasm, dna integration, dna recombination, dna-directed dna polymerase, endonuclease, lipoprotein, magnesium, metal-binding, multifunctional enzyme, myristate, nuclease, nucleotidyltransferase, nucleus, phosphoprotein, protease, ribosomal frameshifting, rna-binding, rna-directed dna polymerase, transferase, viral nucleoprotein, virion, zinc, zinc-finger
• Biological source: Human immunodeficiency virus type 1 (HIV-1)
• Cellular location: Gag-Pol polyprotein: Host cell membrane ; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03367
• Total number of polymer chains: 2
• Total formula weight: 22187.40

Authors

Wang, Y.F.,Weber, I.T. (deposition date: 2008-06-24, release date: 2009-05-12, Last modification date: 2023-11-01)

Primary citation

Ghosh, A.K.,Gemma, S.,Takayama, J.,Baldridge, A.,Leshchenko-Yashchuk, S.,Miller, H.B.,Wang, Y.F.,Kovalevsky, A.Y.,Koh, Y.,Weber, I.T.,Mitsuya, H.
Potent HIV-1 protease inhibitors incorporating meso-bicyclic urethanes as P2-ligands: structure-based design, synthesis, biological evaluation and protein-ligand X-ray studies
Org.Biomol.Chem., 6:3703-3713, 2008

PubMed Abstract: Recently, we designed a series of novel HIV-1 protease inhibitors incorporating a stereochemically defined bicyclic fused cyclopentyl (Cp-THF) urethane as the high affinity P2-ligand. Inhibitor with this P2-ligand has shown very impressive potency against multi-drug-resistant clinical isolates. Based upon the -bound HIV-1 protease X-ray structure, we have now designed and synthesized a number of meso-bicyclic ligands which can conceivably interact similarly to the Cp-THF ligand. The design of meso-ligands is quite attractive as they do not contain any stereocenters. Inhibitors incorporating urethanes of bicyclic-1,3-dioxolane and bicyclic-1,4-dioxane have shown potent enzyme inhibitory and antiviral activities. Inhibitor (K(i) = 0.11 nM; IC(50) = 3.8 nM) displayed very potent antiviral activity in this series. While inhibitor showed comparable enzyme inhibitory activity (K(i) = 0.18 nM) its antiviral activity (IC(50) = 170 nM) was significantly weaker than inhibitor . Inhibitor maintained an antiviral potency against a series of multi-drug resistant clinical isolates comparable to amprenavir. A protein-ligand X-ray structure of -bound HIV-1 protease revealed a number of key hydrogen bonding interactions at the S2-subsite. We have created an active model of inhibitor based upon this X-ray structure.

PubMed: 18843400
DOI: 10.1039/b809178a

Experimental method

X-RAY DIFFRACTION (1.07 Å)