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© Research
Publication : European journal of medicinal chemistry

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in European journal of medicinal chemistry - 05 Dec 2021

Song L, Merceron R, Hulpia F, Lucía A, Gracia B, Jian Y, Risseeuw MDP, Verstraelen T, Cos P, Aínsa JA, Boshoff HI, Munier-Lehmann H, Savvides SN, Van Calenbergh S,

Link to Pubmed [PMID] – 34450493

Link to DOI – S0223-5234(21)00633-410.1016/j.ejmech.2021.113784

Eur J Med Chem 2021 Dec; 225(): 113784

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.

https://pubmed.ncbi.nlm.nih.gov/34450493