129623 20250313085414.0 doi 10.1016/j.ejmech.2021.113784 sideral 126760 ART-2021-126760 eng Song L. Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors 2021 Access copy available to the general public Unrestricted Mycobacterium tuberculosis thymidylate kinase (MtTMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside MtTMPK inhibitors in an effort to diversify MtTMPK inhibitor chemical space. We here report a new series of MtTMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of MtTMPK in complex with developed inhibitors. These efforts furnished the most potent MtTMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the MtTMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. © 2021 Elsevier Masson SAS info:eu-repo/semantics/openAccess by-nc-nd http://creativecommons.org/licenses/by-nc-nd/3.0/es/ 7.088 2021 CHEMISTRY, MEDICINAL 5 / 63 = 0.079 2021 Q1 T1 1.054 2021 Drug Discovery 2021 Q1 Pharmacology 2021 Q1 Medicine (miscellaneous) 2021 Q1 11.2 2021 info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Merceron R. Hulpia F. Lucía A. Universidad de Zaragoza (orcid)0000-0002-0111-4697 Gracia B. Universidad de Zaragoza (orcid)0000-0001-9233-5024 Jian Y. Risseeuw M.D.P. Verstraelen T. Cos P. Aínsa J.A. Universidad de Zaragoza (orcid)0000-0003-2076-844X Boshoff H.I. Munier-Lehmann H. Savvides S.N. Van Calenbergh S. 1011 630 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Microbiología 1011 X Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Proy. investigación HQA 225 (2021), 137842 [25 pp] Eur. j. med. chem. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 0223-5234 2432445 http://zaguan.unizar.es/record/129623/files/texto_completo.pdf Postprint 1439317 http://zaguan.unizar.es/record/129623/files/texto_completo.jpg?subformat=icon icon Postprint oai:zaguan.unizar.es:129623 articulos driver 2025-03-13-08:43:51 ARTICLE