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Fragment-sized EthR inhibitors exhibit exceptionally strong ethionamide boosting effect in whole cell Mycobacterium tuberculosis assays.

Publications by the Blundell group - Tue, 21/03/2017 - 04:09
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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

Abstract
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]

Categories: Publications

DNA-PKcs structure suggests an allosteric mechanism modulating DNA double-strand break repair.

Publications by the Blundell group - Tue, 14/03/2017 - 09:51
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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

Abstract
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]

Categories: Publications

Does a more precise chemical description of protein-ligand complexes lead to more accurate prediction of binding affinity?

Publications by Adrian Schreyer - Tue, 14/03/2017 - 08:44
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Does a more precise chemical description of protein-ligand complexes lead to more accurate prediction of binding affinity?

J Chem Inf Model. 2014 Mar 24;54(3):944-55

Authors: Ballester PJ, Schreyer A, Blundell TL

Abstract
Predicting the binding affinities of large sets of diverse molecules against a range of macromolecular targets is an extremely challenging task. The scoring functions that attempt such computational prediction are essential for exploiting and analyzing the outputs of docking, which is in turn an important tool in problems such as structure-based drug design. Classical scoring functions assume a predetermined theory-inspired functional form for the relationship between the variables that describe an experimentally determined or modeled structure of a protein-ligand complex and its binding affinity. The inherent problem of this approach is in the difficulty of explicitly modeling the various contributions of intermolecular interactions to binding affinity. New scoring functions based on machine-learning regression models, which are able to exploit effectively much larger amounts of experimental data and circumvent the need for a predetermined functional form, have already been shown to outperform a broad range of state-of-the-art scoring functions in a widely used benchmark. Here, we investigate the impact of the chemical description of the complex on the predictive power of the resulting scoring function using a systematic battery of numerical experiments. The latter resulted in the most accurate scoring function to date on the benchmark. Strikingly, we also found that a more precise chemical description of the protein-ligand complex does not generally lead to a more accurate prediction of binding affinity. We discuss four factors that may contribute to this result: modeling assumptions, codependence of representation and regression, data restricted to the bound state, and conformational heterogeneity in data.

PMID: 24528282 [PubMed - indexed for MEDLINE]

Structure-guided, target-based drug discovery - exploiting genome information from HIV to mycobacterial infections.

Publications by the Blundell group - Tue, 31/01/2017 - 21:15
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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

Abstract
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]

Categories: Publications
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