Abstract:
:Infections caused by Enterococcus faecalis (Ef) represent nowadays a relevant health problem. We selected Thymidylate synthase (TS) from this organism as a potential specific target for antibacterial therapy. We have previously demonstrated that species-specific inhibition of the protein can be achieved despite the relatively high structural similarity among bacterial TSs and human TS. We had previously obtained the EfTS crystal structure of the protein in complex with the metabolite 5-formyl-tetrahydrofolate (5-FTHF) suggesting the protein role as metabolite reservoir; however, protein-inhibitors complexes were still missing. In the present work we identified some inhibitors bearing the phthalimidic core from our in-house library and we performed crystallographic screening towards EfTS. We obtained two X-ray crystallographic structures: the first with a weak phthalimidic inhibitor bound in one subunit and 5-hydroxymethylene-6-hydrofolic acid (5-HMHF) in the other subunit; a second X-ray structure complex with methotrexate. The structural information achieved confirm the role of EfTS as an enzyme involved in the folate pool system and provide a structural basis for structure-based drug design.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Catalano A,Luciani R,Carocci A,Cortesi D,Pozzi C,Borsari C,Ferrari S,Mangani Sdoi
10.1016/j.ejmech.2016.07.066subject
Has Abstractpub_date
2016-11-10 00:00:00pages
649-664eissn
0223-5234issn
1768-3254pii
S0223-5234(16)30631-6journal_volume
123pub_type
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