5nim › Citations

New active leads for tuberculosis booster drugs by structure-based drug discovery.

Tatum NJ, Liebeschuetz JW, Cole JC, Frita R, Herledan A, Baulard AR, Willand N, Pohl E
Org Biomol Chem 15 10245-10255 (2017)
Related entries: 5nio, 5niz, 5nj0

Cited: 11 times
EuropePMC logo PMID: 29182187

Abstract

The transcriptional repressor EthR from Mycobacterium tuberculosis, a member of the TetR family of prokaryotic homo-dimeric transcription factors, controls the expression of the mycobacterial mono-oxygenase EthA. EthA is responsible for the bio-activation of the second-line tuberculosis pro-drug ethionamide, and consequently EthR inhibitors boost drug efficacy. Here, we present a comprehensive in silico structure-based screening protocol that led to the identification of a number of novel scaffolds of EthR inhibitors in subsequent biophysical screening by thermal shift assay. Growth inhibition assays demonstrated that five of the twenty biophysical hits were capable of boosting ethionamide activity in vitro, with the best novel scaffold displaying an EC50 of 34 μM. In addition, the co-crystal structures of EthR with four new ligands at resolution ranging from 2.1 to 1.4 Å confirm the binding and inactivation mode, and will enable future lead development.

Reviews citing this publication (2)

  1. Drug Discovery for Mycobacterium tuberculosis Using Structure-Based Computer-Aided Drug Design Approach. Ejalonibu MA, Ogundare SA, Elrashedy AA, Ejalonibu MA, Lawal MM, Mhlongo NN, Kumalo HM. Int J Mol Sci 22 13259 (2021)
  2. Structure-based in silico approaches for drug discovery against Mycobacterium tuberculosis. Kingdon ADH, Alderwick LJ. Comput Struct Biotechnol J 19 3708-3719 (2021)

Articles citing this publication (9)

  1. High throughput virtual screening reveals SARS-CoV-2 multi-target binding natural compounds to lead instant therapy for COVID-19 treatment. Naik B, Gupta N, Ojha R, Singh S, Prajapati VK, Prusty D. Int J Biol Macromol 160 1-17 (2020)
  2. AmiP from hyperthermophilic Thermus parvatiensis prophage is a thermoactive and ultrathermostable peptidoglycan lytic amidase. Jasilionis A, Plotka M, Wang L, Dorawa S, Lange J, Watzlawick H, van den Bergh T, Vroling B, Altenbuchner J, Kaczorowska AK, Pohl E, Kaczorowski T, Nordberg Karlsson E, Freitag-Pohl S. Protein Sci 32 e4585 (2023)
  3. GSP4PDB: a web tool to visualize, search and explore protein-ligand structural patterns. Angles R, Arenas-Salinas M, García R, Reyes-Suarez JA, Pohl E. BMC Bioinformatics 21 85 (2020)
  4. Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds. Tatum NJ, Duarte F, Kamerlin SCL, Pohl E. J Phys Chem Lett 10 2244-2249 (2019)
  5. Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening. Denny PW. Expert Opin Drug Discov 13 1153-1160 (2018)
  6. Hit Compounds and Associated Targets in Intracellular Mycobacterium tuberculosis. Tsui CKM, Sorrentino F, Narula G, Mendoza-Losana A, Del Rio RG, Herrán EP, Lopez A, Bojang A, Zheng X, Remuiñán-Blanco MJ, Av-Gay Y. Molecules 27 4446 (2022)
  7. Molecular Determinants of Ethionamide Resistance in Clinical Isolates of Mycobacterium tuberculosis. Ushtanit A, Kulagina E, Mikhailova Y, Makarova M, Safonova S, Zimenkov D. Antibiotics (Basel) 11 133 (2022)
  8. Probing biological activity through structural modelling of ligand-receptor interactions of 2,4-disubstituted thiazole retinoids. Haffez H, Chisholm DR, Tatum NJ, Valentine R, Redfern C, Pohl E, Whiting A, Przyborski S. Bioorg. Med. Chem. 26 1560-1572 (2018)
  9. Screening of Buffers and Additives for Protein Stabilization by Thermal Shift Assay: A Practical Approach. Engrola FSS, Paquete-Ferreira J, Santos-Silva T, Correia MAS, Leisico F, Santos MFA. Methods Mol Biol 2652 199-213 (2023)


Quick links