X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors

Catalano, Alessia; Luciani, Rosaria; Carocci, Alessia; Cortesi, Debora; Pozzi, Cecilia; Borsari, Chiara; Ferrari, Stefania; Mangani, Stefano

doi:10.1016/j.ejmech.2016.07.066

Cited by 17 publications

(17 citation statements)

References 69 publications

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“…Bacterial TS enzymes represent a validated target for the development of antimicrobial drugs. In the past years, various classes of inhibitors have been explored for bacterial TSs, some of them specifically targeting Enterococcus faecalis TS, such as phtalimide-derivatives [43,44]. The most active phtalimide inhibitors of Ef TS showed selectivity towards the human counterpart enzyme [44].…”

Section: Discussionmentioning

confidence: 99%

“…The structure of Ef TS in complex with a representative phtalimide inhibitor (PDB id 4O7U [44]) showed close van der Waals contact between the six-membered aromatic ring of phtalimide and Trp84, explaining the selectivity profile of these molecules. Trp84 of Ef TS is also conserved in TSs of other human pathogens, such as M. tuberculosis and S. aureus , providing a clue for the design of new selective bacterial TSs inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Structural Comparison of Enterococcus faecalis and Human Thymidylate Synthase Complexes with the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities

et al. 2019

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Thymidylate synthase (TS) is an enzyme of paramount importance as it provides the only de novo source of deoxy-thymidine monophosphate (dTMP). dTMP, essential for DNA synthesis, is produced by the TS-catalyzed reductive methylation of 2′-deoxyuridine-5′-monophosphate (dUMP) using N5,N10-methylenetetrahydrofolate (mTHF) as a cofactor. TS is ubiquitous and a validated drug target. TS enzymes from different organisms differ in sequence and structure, but are all obligate homodimers. The structural and mechanistic differences between the human and bacterial enzymes are exploitable to obtain selective inhibitors of bacterial TSs that can enrich the currently available therapeutic tools against bacterial infections. Enterococcus faecalis is a pathogen fully dependent on TS for dTMP synthesis. In this study, we present four new crystal structures of Enterococcus faecalis and human TSs in complex with either the substrate dUMP or the inhibitor FdUMP. The results provide new clues about the half-site reactivity of Enterococcus faecalis TS and the mechanisms underlying the conformational changes occurring in the two enzymes. We also identify relevant differences in cofactor and inhibitor binding between Enterococcus faecalis and human TS that can guide the design of selective inhibitors against bacterial TSs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structural Comparison of Enterococcus faecalis and Human Thymidylate Synthase Complexes with the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities

et al. 2019

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“…Compounds 1 , 7 , 2 , 3 , and 6 (Figure ) were prepared as described elsewhere. Chiral compounds ( 3 , 4 , 6 , 8 ) were prepared in their racemic forms.…”

Section: Chemistrymentioning

confidence: 99%

“…Compounds 1, 7, [22] 2, [23] 3,a nd 6 [24] (Figure 1) were prepared as described elsewhere. Chiral compounds (3,4,6,8)wereprepared in their racemic forms.C ompound 4 was prepared as shown in Scheme 1.…”

Section: Chemistrymentioning

confidence: 99%

Old Drug Scaffold, New Activity: Thalidomide‐Correlated Compounds Exert Different Effects on Breast Cancer Cell Growth and Progression

et al. 2017

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Thalidomide was first used for relief of morning sickness in pregnant women and then withdrawn from the market because of its dramatic effects on normal fetal development. Over the last decades, it has been used successfully for the treatment of several pathologies, including cancer. Many analogues with improved activity have been synthesized and tested. Herein we report some effects on the growth and progression of MCF-7 and MDA-MB-231 breast cancer cells by a small series of thalidomide-correlated compounds, which are very effective at inducing cancer cell death by triggering TNFα-mediated apoptosis. The most active compounds are able to drastically reduce the migration of breast cancer cells by regulation of the two major proteins involved in epithelial-mesenchymal transition (EMT): vimentin and E-cadherin. Moreover, these compounds diminish the intracellular biosynthesis of vascular endothelial growth factor (VEGF), which is primarily involved in the promotion of angiogenesis, sustaining tumor progression. The multiple features of these compounds that act on various key points of the tumorigenesis process make them good candidates for preclinical studies.

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“…3,4 TS is responsible for the formation of deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) which is further phosphorylated to triphosphate group (dTTP), a direct precursor for DNA synthesis. [5][6][7] TS inhibition causes inhibition of thymidylate biosynthesis which in turn causes cessation of cell growth and proliferation. 8,9 Research on TS has been going on since many years, but still it is a challenge for medicinal chemists to develop new, safe and effective chemotherapeutic agents as TS inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis andin vitroantiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors

Alzhrani

Alam

Neamatallah

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Thymidylate synthase (TS) has been an attention-grabbing area of research for the treatment of cancers due to their role in DNA biosynthesis. In the present study, we have synthesised a library of thiazolidinedione-1,3,4-oxadiazole hybrids as TS inhibitors. All the synthesised hybrids followed Lipinski and Veber rules which indicated good drug likeness properties upon oral administration. Among the synthesised hybrids, compound 9 and 10 displayed 4.5 and 4.4 folds activity of 5-Fluorouracil, respectively against MCF-7 cell line whereas 3.1 and 2.5 folds cytotoxicity against HCT-116 cell line. Furthermore, compound 9 and 10 also inhibited TS enzyme with IC 50 ¼ 1.67 and 2.21 mM, respectively. Finally, the docking studies of 9 and 10 were found to be consistent with in vitro TS results. From these studies, compound 9 and 10 has the potential to be developed as TS inhibitors.

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X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors

Cited by 17 publications

References 69 publications

Structural Comparison of Enterococcus faecalis and Human Thymidylate Synthase Complexes with the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities

Structural Comparison of Enterococcus faecalis and Human Thymidylate Synthase Complexes with the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities

Old Drug Scaffold, New Activity: Thalidomide‐Correlated Compounds Exert Different Effects on Breast Cancer Cell Growth and Progression

Design, synthesis andin vitroantiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors

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