4E28

Structure of human thymidylate synthase in inactive conformation with a novel non-peptidic inhibitor

Summary for 4E28

• Entry DOI: 10.2210/pdb4e28/pdb
• Related: 3EGY 3EHI
• Descriptor: Thymidylate synthase, SULFATE ION, 2-{(2Z,5S)-4-hydroxy-2-[(2E)-(2-hydroxybenzylidene)hydrazinylidene]-2,5-dihydro-1,3-thiazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide, ... (5 entities in total)
• Functional Keywords: human thymidylate synthase (hts) inactive conformation, hts-inhibitor complex, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P04818
• Total number of polymer chains: 1
• Total formula weight: 38385.63

Authors

Tochowicz, A.,Finer-Moore, J.,Stroud, R.M.,Costi, M.P. (deposition date: 2012-03-07, release date: 2012-11-14, Last modification date: 2023-09-13)

Primary citation

Carosati, E.,Tochowicz, A.,Marverti, G.,Guaitoli, G.,Benedetti, P.,Ferrari, S.,Stroud, R.M.,Finer-Moore, J.,Luciani, R.,Farina, D.,Cruciani, G.,Costi, M.P.
Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase.
J.Med.Chem., 55:10272-10276, 2012

PubMed Abstract: Human thymidylate synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed a mixed-type inhibition pattern, with a K(i) of 1.3 μM and activity against ovarian cancer cell lines with the same potency as cisplatin. X-ray studies revealed that it binds the inactive enzyme conformation. This study is the first example of a nonpeptidic inhibitor that binds the inactive hTS and exhibits anticancer activity against ovarian cancer cells.

PubMed: 23075414
DOI: 10.1021/jm300850v

Experimental method

X-RAY DIFFRACTION (2.302 Å)