3DK1: Wild Type Hiv-1 Protease With Potent Antiviral Inhibitor Grl-0105a

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.
PDB ID: 3DK1Download
MMDB ID: 72588
PDB Deposition Date: 2008/6/24
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.07  Å
Source Organism:
Similar Structures:
Biological Unit for 3DK1: dimeric; determined by author and by software (PISA)
Molecular Components in 3DK1
Label Count Molecule
Proteins (2 molecules)
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB