5T9Z
Discovery of a Potent Cyclophilin Inhibitor (Compound 6) based on Structural Simplification of Sanglifehrin A
Summary for 5T9Z
Entry DOI | 10.2210/pdb5t9z/pdb |
Related | 5T9W 5TA2 5TA4 |
Related PRD ID | PRD_002245 |
Descriptor | Peptidyl-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 Keywords | cyclophilin inhibitor antiviral hcv, isomerase-isomerase inhibitor complex, isomerase/isomerase inhibitor |
Biological source | Homo sapiens (Human) |
Cellular location | Cytoplasm : P62937 |
Total number of polymer chains | 1 |
Total formula weight | 18410.95 |
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 citation | Steadman, 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: 28075591DOI: 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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