8V17
HIV-CA Disulfide linked Hexamer with inhibitor bound - exploration of a benzothiazole
Summary for 8V17
| Entry DOI | 10.2210/pdb8v17/pdb |
| Descriptor | Spacer peptide 1, N-(1,3-benzothiazol-5-yl)-3,5-difluoro-Nalpha-[(5-hydroxy-1H-indol-3-yl)acetyl]-N-methyl-L-phenylalaninamide, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | hiv-1, human immunodeficiency virus, capsid, hiv-ca, capsid inhibitor, hiv restriction, viral protein, viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 1 |
| Total formula weight | 26045.81 |
| Authors | |
| Primary citation | Xu, S.,Wang, S.,Zhou, Y.,Foley, N.,Sun, L.,Walsham, L.,Tang, K.,Shi, D.,Shi, X.,Zhang, Z.,Jiang, X.,Gao, S.,Liu, X.,Pannecouque, C.,Goldstone, D.C.,Dick, A.,Zhan, P. "Pseudosubstrate Envelope"/Free Energy Perturbation-Guided Design and Mechanistic Investigations of Benzothiazole HIV Capsid Modulators with High Ligand Efficiency. J.Med.Chem., 67:19057-19076, 2024 Cited by PubMed Abstract: Based on our proposed "pseudosubstrate envelope" concept, 25 benzothiazole-bearing HIV capsid protein (CA) modulators were designed and synthesized under the guidance of free energy perturbation technology. The most potent compound, , exhibited an EC of 2.69 nM against HIV-1, being 393 times more potent than the positive control PF74. Notably, emerged as the highest ligand efficiency (LE = 0.32) HIV CA modulator, surpassing that of the approved drug lenacapavir (LE = 0.21). Surface plasmon resonance assay and crystallographic analysis confirmed that targeted HIV-1 CA within the chemical space of the "pseudosubstrate envelope". Further mechanistic studies revealed a dual-stage inhibition profile: disrupted early-stage capsid-host-factor interactions and promoted late-stage capsid misassembly. Preliminary pharmacokinetic evaluations demonstrated significantly improved metabolic stability in human liver microsomes for ( = 91.3 min) compared to PF74 ( = 0.7 min), alongside a favorable safety profile. Overall, presents a promising lead compound for further optimization. PubMed: 39418501DOI: 10.1021/acs.jmedchem.4c01544 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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