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5T9Z

Discovery of a Potent Cyclophilin Inhibitor (Compound 6) based on Structural Simplification of Sanglifehrin A

Summary for 5T9Z
Entry DOI10.2210/pdb5t9z/pdb
Related5T9W 5TA2 5TA4
Related PRD IDPRD_002245
DescriptorPeptidyl-prolyl cis-trans isomerase A, 11-[(3-hydroxyphenyl)methyl]-18-methoxy-17-methyl-14-(propan-2-yl)-3-oxa-9,12,15,28-tetraazatricyclo[21.3.1.1~5,9~]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetrone (3 entities in total)
Functional Keywordscyclophilin inhibitor antiviral hcv, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor
Biological sourceHomo sapiens (Human)
Cellular locationCytoplasm : P62937
Total number of polymer chains1
Total formula weight18410.95
Authors
Appleby, T.C.,Steadman, V.,Pettit, S.,Schmitz, U.,Mackman, R.L.,Schultz, B. (deposition date: 2016-09-09, release date: 2017-01-25, Last modification date: 2024-03-06)
Primary citationSteadman, V.A.,Pettit, S.B.,Poullennec, K.G.,Lazarides, L.,Keats, A.J.,Dean, D.K.,Stanway, S.J.,Austin, C.A.,Sanvoisin, J.A.,Watt, G.M.,Fliri, H.G.,Liclican, A.C.,Jin, D.,Wong, M.H.,Leavitt, S.A.,Lee, Y.J.,Tian, Y.,Frey, C.R.,Appleby, T.C.,Schmitz, U.,Jansa, P.,Mackman, R.L.,Schultz, B.E.
Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A.
J. Med. Chem., 60:1000-1017, 2017
Cited by
PubMed Abstract: Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency. Replacing the C18-C21 diene unit of sanglifehrin with a styryl group led to potent compounds that displayed a novel binding mode in which the styrene moiety engaged in a π-stacking interaction with Arg55 of cyclophilin A (Cyp A), and the m-Tyr residue was displaced into solvent. This observation allowed further simplifications of the scaffold to generate new lead compounds in the search for orally bioavailable cyclophilin inhibitors.
PubMed: 28075591
DOI: 10.1021/acs.jmedchem.6b01329
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.4 Å)
Structure validation

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