Fragment-sized EthR inhibitors exhibit exceptionally strong ethionamide boosting effect in whole cell Mycobacterium tuberculosis assays.
ACS Chem Biol. 2017 Mar 17;:
Authors: Nikiforov PO, Blaszczyk M, Surade S, Boshoff HI, Sajid A, Delorme V, Deboosere N, Brodin P, Baulard AR, Barry Rd CE, Blundell TL, Abell C
Small molecule inhibitors of the mycobacterial transcriptional repressor EthR have previously been shown to act as boosters of the second-line antituberculosis drug ethionamide. Fragment-based drug discovery approaches have been used in the past to make highly potent EthR inhibitors with ethionamide boosting activity both in vitro and ex vivo. Herein, we report the development of fragment-sized EthR ligands with nanomolar minimum effective concentration (MEC) values for the boosting of ethionamide activity in M. tuberculosis whole cell assays.
PMID: 28314097 [PubMed - as supplied by publisher]
DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair.
Science. 2017 Feb 03;355(6324):520-524
Authors: Sibanda BL, Chirgadze DY, Ascher DB, Blundell TL
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a central component of nonhomologous end joining (NHEJ), repairing DNA double-strand breaks that would otherwise lead to apoptosis or cancer. We have solved its structure in complex with the C-terminal peptide of Ku80 at 4.3 angstrom resolution using x-ray crystallography. We show that the 4128-amino acid structure comprises three large structural units: the N-terminal unit, the Circular Cradle, and the Head. Conformational differences between the two molecules in the asymmetric unit are correlated with changes in accessibility of the kinase active site, which are consistent with an allosteric mechanism to bring about kinase activation. The location of KU80ct194 in the vicinity of the breast cancer 1 (BRCA1) binding site suggests competition with BRCA1, leading to pathway selection between NHEJ and homologous recombination.
PMID: 28154079 [PubMed - in process]
Structure-guided, target-based drug discovery - exploiting genome information from HIV to mycobacterial infections.
Postepy Biochem. 2016;62(3):262-272
Authors: Malhotra S, Thomas SE, Ochoa Montano B, Blundell TL
The use of protein crystallography in structure-guided drug discovery allows identification of potential inhibitor-binding sites and optimisation of interactions of hits and lead compounds with a target protein. An early example of this approach was the use of the structure of HIV protease in designing AIDS antivirals. More recently, use of structure-guided design with fragment-based drug discovery, which reduces the size of screening libraries by decreasing complexity, has improved ligand efficiency in drug design. Here, we discuss the use of structure-guided target identification and lead optimisation using fragment-based approaches in the development of new antimicrobials for mycobacterial infections.
PMID: 28132480 [PubMed - in process]