PDBsum entry 6d4t

Oxidoreductase/oxidoreductase inhibitor

PDB id: 6d4t

Contents

Protein chain

331 a.a.

Ligands

IMP

FWS

Waters ×298

PDB id:

6d4t

Name:

Oxidoreductase/oxidoreductase inhibitor

Title:

M. Thermoresistible guab2 delta-cbs in complex with inhibitor compound 45 (vcc117054)

Structure:

Inosine-5'-monophosphate dehydrogenase,inosine-5'- monophosphate dehydrogenase. Chain: a. Synonym: impdh,impdh. Engineered: yes

Source:

Mycobacterium thermoresistibile. Organism_taxid: 1078020. Strain: atcc 19527 / dsm 44167 / cip 105390 / jcm 6362 / nctc 10409 / 316. Gene: guab, kek_23061. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.54Å R-factor: 0.166 R-free: 0.187

Authors:

D.B.Ascher,A.Pacitto,T.L.Blundell

Key ref:

V.Singh et al. (2019). Synthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH. Eur J Med Chem, 174, 309-329. PubMed id: 31055147 DOI: 10.1016/j.ejmech.2019.04.027

Date:

18-Apr-18 Release date: 01-May-19

Protein chain

G7CNL4  (G7CNL4_MYCT3) -  Inosine-5'-monophosphate dehydrogenase from Mycolicibacterium thermoresistibile (strain ATCC 19527 / DSM 44167 / CIP 105390 / JCM 6362 / NCTC 10409 / 316)

Seq: 513 a.a.

Struc: 331 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.1.1.1.205 - Imp dehydrogenase.
• Pathway: AMP and GMP Biosynthesis
• Reaction: IMP + NAD⁺ + H2O = XMP + NADH + H⁺

IMP + NAD(+) (Bound ligand (Het Group name = IMP) corresponds exactly) + H2O = XMP + NADH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.ejmech.2019.04.027

Eur J Med Chem 174:309-329 (2019)

PubMed id: 31055147

Synthesis and Structure-Activity relationship of 1-(5-isoquinolinesulfonyl)piperazine analogues as inhibitors of Mycobacterium tuberculosis IMPDH.

V.Singh, A.Pacitto, S.Donini, D.M.Ferraris, S.Boros, E.Illyés, B.Szokol, M.Rizzi, T.L.Blundell, D.B.Ascher, J.Pato, V.Mizrahi.

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.