Structure-aided optimization of non-nucleoside M. tuberculosis thymidylate kinase inhibitors

Song L. ; Merceron R. ; Hulpia F. ; Lucía A. (Universidad de Zaragoza) ; Gracia B. (Universidad de Zaragoza) ; Jian Y. ; Risseeuw M.D.P. ; Verstraelen T. ; Cos P. ; Aínsa J.A. (Universidad de Zaragoza) ; Boshoff H.I. ; Munier-Lehmann H. ; Savvides S.N. ; Van Calenbergh S.

Resumen: 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

Idioma: Inglés

DOI: 10.1016/j.ejmech.2021.113784

Año: 2021

Publicado en: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 225 (2021), 137842 [25 pp]
ISSN: 0223-5234

Factor impacto JCR: 7.088 (2021)

Categ. JCR: CHEMISTRY, MEDICINAL rank: 5 / 63 = 0.079 (2021) - Q1 - T1

Factor impacto CITESCORE: 11.2 - Pharmacology, Toxicology and Pharmaceutics (Q1) - Medicine (Q1)

Factor impacto SCIMAGO: 1.054 - Drug Discovery (Q1) - Pharmacology (Q1) - Medicine (miscellaneous) (Q1)

Tipo y forma: Article (PostPrint)

Área (Departamento): Área Microbiología (Dpto. Microb.Ped.Radio.Sal.Pú.)
Área (Departamento): Proy. investigación HQA (Dpto. Microb.Ped.Radio.Sal.Pú.)