5voj | pdb_00005voj

Crystal structure of HCV NS3/4A protease in complex with JZ01-15, an analogue of 5172-mcP1P3

spinqualitylabelsall models 5voj, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5voj is a 1 chain structure with sequence from Hepatitis c virus subtype 1a. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 9H4, SO4, ZN Related: 5vp9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values </=5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance. Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants.,Matthew AN, Zephyr J, Hill CJ, Jahangir M, Newton A, Petropoulos CJ, Huang W, Kurt-Yilmaz N, Schiffer CA, Ali A J Med Chem. 2017 Jul 13;60(13):5699-5716. doi: 10.1021/acs.jmedchem.7b00426. Epub, 2017 Jun 19. PMID:28594175 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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