8I67

Crystal structure of Mycobacterium tuberculosis Uracil-DNA glycosylase in complex with 2,4-Thiazolidinedione, Form I

Summary for 8I67

• Entry DOI: 10.2210/pdb8i67/pdb
• Descriptor: Uracil-DNA glycosylase, 1,3-thiazolidine-2,4-dione, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: dna repair, base excision repair, inhibitor-complex, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Mycobacterium tuberculosis H37Rv
• Total number of polymer chains: 1
• Total formula weight: 25992.74

Authors

Raj, P.,Paul, A.,Gopal, B. (deposition date: 2023-01-27, release date: 2023-07-12, Last modification date: 2024-05-08)

Primary citation

Kesharwani, S.,Raj, P.,Paul, A.,Roy, K.,Bhanot, A.,Mehta, A.,Gopal, A.,Varshney, U.,Gopal, B.,Sundriyal, S.
Crystal structures of non-uracil ring fragments in complex with Mycobacterium tuberculosis uracil DNA glycosylase (MtUng) as a starting point for novel inhibitor design: A case study with the barbituric acid fragment.
Eur.J.Med.Chem., 258:115604-115604, 2023

PubMed Abstract: Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC = 300 μM) displaying ∼24-fold potency over the uracil ring.

PubMed: 37399710
DOI: 10.1016/j.ejmech.2023.115604

Experimental method

X-RAY DIFFRACTION (1.72 Å)