7wbs

Crystal structure of HIV-1 protease in complex with lactam derivative 2

spinqualitylabelsall models 7wbs, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7wbs is a 2 chain structure with sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: 8LT, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9WFL7_9HIV1 Publication Abstract from PubMed A novel strategy for lead identification that we have dubbed the "Pocket-to-Lead" strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized in silico. The designed compound 9 demonstrated weak but evident inhibitory activity (IC50 = 54 muM), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound 14 (IC50 = 0.0071 muM, EC50 = 0.86 muM), an almost 10,000-fold improvement in activity from 9. The structure of the designed molecules proved to be novel with high synthetic feasibility, indicating the usefulness of this strategy to tackle tough targets with complex pharmacophore. Pocket-to-Lead: Structure-Based De Novo Design of Novel Non-peptidic HIV-1 Protease Inhibitors Using the Ligand Binding Pocket as a Template.,Kojima E, Iimuro A, Nakajima M, Kinuta H, Asada N, Sako Y, Nakata Z, Uemura K, Arita S, Miki S, Wakasa-Morimoto C, Tachibana Y J Med Chem. 2022 Apr 28;65(8):6157-6170. doi: 10.1021/acs.jmedchem.1c02217. Epub , 2022 Apr 13. PMID:35416651 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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