4ZLS
HIV-1 wild Type protease with GRL-096-13A (a Boc-derivative P2-Ligand, 3,-5-dimethylbiphenyl P1-Ligand)
Summary for 4ZLS
| Entry DOI | 10.2210/pdb4zls/pdb |
| Related | 2IEN 3OK9 3QAA 4U8W |
| Descriptor | Protease, SODIUM ION, CHLORIDE ION, ... (6 entities in total) |
| Functional Keywords | multidrug-resistant strains, hydrolase inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Human immunodeficiency virus type 1 BH10 (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 : P03366 |
| Total number of polymer chains | 2 |
| Total formula weight | 22312.55 |
| Authors | Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2015-05-01, release date: 2015-07-15, Last modification date: 2023-09-27) |
| Primary citation | Ghosh, A.K.,Yu, X.,Osswald, H.L.,Agniswamy, J.,Wang, Y.F.,Amano, M.,Weber, I.T.,Mitsuya, H. Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme-Inhibitor X-ray Structural Studies. J.Med.Chem., 58:5334-5343, 2015 Cited by PubMed Abstract: We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease. PubMed: 26107245DOI: 10.1021/acs.jmedchem.5b00676 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.53 Å) |
Structure validation
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