6D4V

M. thermoresistible GuaB2 delta-CBS in complex with inhibitor Compound 22 (VCC061422)

Summary for 6D4V

• Entry DOI: 10.2210/pdb6d4v/pdb
• Descriptor: Inosine-5'-monophosphate dehydrogenase,Inosine-5'-monophosphate dehydrogenase, INOSINIC ACID, 2-cyclohexyl-1-{4-[(isoquinolin-5-yl)sulfonyl]piperazin-1-yl}ethan-1-one, ... (4 entities in total)
• Functional Keywords: complex, fragment, impdh, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Mycobacterium thermoresistibile; More
• Total number of polymer chains: 1
• Total formula weight: 40604.20

Authors

Ascher, D.B.,Pacitto, A.,Blundell, T.L. (deposition date: 2018-04-18, release date: 2019-05-01, Last modification date: 2023-10-04)

Primary citation

Singh, V.,Pacitto, A.,Donini, S.,Ferraris, D.M.,Boros, S.,Illyes, E.,Szokol, B.,Rizzi, M.,Blundell, T.L.,Ascher, D.B.,Pato, J.,Mizrahi, V.
Synthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH.
Eur.J.Med.Chem., 174:309-329, 2019

PubMed Abstract: Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation.

PubMed: 31055147
DOI: 10.1016/j.ejmech.2019.04.027

Experimental method

X-RAY DIFFRACTION (2.02 Å)