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https://hdl.handle.net/10316/111822
Title: | Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12 | Authors: | Ahonen, Tiina J. Ng, Choa P. Farinha, Beatriz Almeida, Bárbara Victor, Bruno L. Reynolds, Christopher Kalso, Eija Yli-Kauhaluoma, Jari Greaves, Jennifer Moreira, Vânia M. |
Keywords: | ABHD16A; ABHD12; serine hydrolase; dehydroabietic acid; competitive ABPP | Issue Date: | 12-Oct-2023 | Publisher: | American Chemical Society | Project: | Funding was received from the European Union Seventh Framework Programme (FP7/2007-2013), Grant Agreement 602919. J.G. thanks the Academy of Medical Sciences (Grant SBF005\1122) for financial support. T.J.A. thanks Finnish Cultural Foundation for financial support. We thank the Research Centre for Health and Life Sciences and the Doctoral College at Coventry University for stipend and fee support to C.P.N. Work was supported by Center Grants UIDB/04046/ 2020 and UIDP/04046/2020 (to BioISI), from FCT/MCTES Portugal, and by the European Union (Grant TWIN2PIPSA GA 101079147). | Serial title, monograph or event: | ACS Medicinal Chemistry Letters | Volume: | 14 | Issue: | 10 | Abstract: | 12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 μM (55.1 ± 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2' position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure-activity relationships presented herein will inspire future drug discovery efforts in this field. | URI: | https://hdl.handle.net/10316/111822 | ISSN: | 1948-5875 | DOI: | 10.1021/acsmedchemlett.3c00313 | Rights: | openAccess |
Appears in Collections: | FFUC- Artigos em Revistas Internacionais I&D CIBB - Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais |
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