6YT1

Mtb TMK crystal structure in complex with compound 26

Summary for 6YT1

• Entry DOI: 10.2210/pdb6yt1/pdb
• Descriptor: Thymidylate kinase, 2-ethyl-~{N}-[[4-[4-[5-methyl-2,4-bis(oxidanylidene)pyrimidin-1-yl]piperidin-1-yl]phenyl]methyl]-1,2,3,5,6,7,8,8~{a}-octahydroimidazo[1,2-a]pyridine-3-carboxamide, CITRIC ACID, ... (4 entities in total)
• Functional Keywords: kinase activity, inhibitor complex, transferase
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 2
• Total formula weight: 46959.57

Authors

Merceron, R.,De Munck, S.,Jian, Y.,Munier-Lehmann, H.,Van Calenbergh, S.,Savvides, S.N. (deposition date: 2020-04-23, release date: 2020-09-02, Last modification date: 2024-01-24)

Primary citation

Jian, Y.,Merceron, R.,De Munck, S.,Forbes, H.E.,Hulpia, F.,Risseeuw, M.D.P.,Van Hecke, K.,Savvides, S.N.,Munier-Lehmann, H.,Boshoff, H.I.M.,Van Calenbergh, S.
Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents.
Eur.J.Med.Chem., 206:112659-112659, 2020

PubMed Abstract: As the last enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.

PubMed: 32823003
DOI: 10.1016/j.ejmech.2020.112659

Experimental method

X-RAY DIFFRACTION (1.9 Å)