4wye › Citations

Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA.

Dai R, Geders TW, Liu F, Park SW, Schnappinger D, Aldrich CC, Finzel BC
J Med Chem 58 5208-17 (2015)
Related entries: 4wya, 4wyc, 4wyd, 4wyf, 4wyg, 4xew

Cited: 19 times
EuropePMC logo PMID: 26068403

Abstract

The PLP-dependent transaminase (BioA) of Mycobacterium tuberculosis and other pathogens that catalyzes the second step of biotin biosynthesis is a now well-validated target for antibacterial development. Fragment screening by differential scanning fluorimetry has been performed to discover new chemical scaffolds and promote optimization of existing inhibitors. Calorimetry confirms binding of six molecules with high ligand efficiency. Thermodynamic data identifies which molecules bind with the enthalpy driven stabilization preferred in compounds that represent attractive starting points for future optimization. Crystallographic characterization of complexes with these molecules reveals the dynamic nature of the BioA active site. Different side chain conformational states are stabilized in response to binding by different molecules. A detailed analysis of conformational diversity in available BioA structures is presented, resulting in the identification of two states that might be targeted with molecular scaffolds incorporating well-defined conformational attributes. This new structural data can be used as part of a scaffold hopping strategy to further optimize existing inhibitors or create new small molecules with improved therapeutic potential.

Articles - 4wye mentioned but not cited (1)

  1. Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA. Dai R, Geders TW, Liu F, Park SW, Schnappinger D, Aldrich CC, Finzel BC. J Med Chem 58 5208-5217 (2015)


Reviews citing this publication (3)

  1. Theory and applications of differential scanning fluorimetry in early-stage drug discovery. Gao K, Oerlemans R, Groves MR. Biophys Rev 12 85-104 (2020)
  2. Binding thermodynamics discriminates fragments from druglike compounds: a thermodynamic description of fragment-based drug discovery. Williams G, Ferenczy GG, Ulander J, Keserű GM. Drug Discov. Today 22 681-689 (2017)
  3. Target-based drug discovery: Applications of fluorescence techniques in high throughput and fragment-based screening. Kumar V, Chunchagatta Lakshman PK, Prasad TK, Manjunath K, Bairy S, Vasu AS, Ganavi B, Jasti S, Kamariah N. Heliyon 10 e23864 (2024)

Articles citing this publication (15)

  1. Multiple Ligand Unbinding Pathways and Ligand-Induced Destabilization Revealed by WExplore. Dickson A, Lotz SD. Biophys. J. 112 620-629 (2017)
  2. Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis. Liu F, Dawadi S, Maize KM, Dai R, Park SW, Schnappinger D, Finzel BC, Aldrich CC. J. Med. Chem. 60 5507-5520 (2017)
  3. Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives. Venugopala KN, Al-Shar'i NA, Dahabiyeh LA, Hourani W, Deb PK, Pillay M, Abu-Irmaileh B, Bustanji Y, Chandrashekharappa S, Tratrat C, Attimarad M, Nair AB, Sreeharsha N, Shinu P, Haroun M, Kandeel M, Balgoname AA, Venugopala R, Morsy MA. Antibiotics (Basel) 11 831 (2022)
  4. Mind the Metal: A Fragment Library-Derived Zinc Impurity Binds the E2 Ubiquitin-Conjugating Enzyme Ube2T and Induces Structural Rearrangements. Morreale FE, Testa A, Chaugule VK, Bortoluzzi A, Ciulli A, Walden H. J. Med. Chem. 60 8183-8191 (2017)
  5. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy. Xie SC, Metcalfe RD, Dunn E, Morton CJ, Huang SC, Puhalovich T, Du Y, Wittlin S, Nie S, Luth MR, Ma L, Kim MS, Pasaje CFA, Kumpornsin K, Giannangelo C, Houghton FJ, Churchyard A, Famodimu MT, Barry DC, Gillett DL, Dey S, Kosasih CC, Newman W, Niles JC, Lee MCS, Baum J, Ottilie S, Winzeler EA, Creek DJ, Williamson N, Parker MW, Brand S, Langston SP, Dick LR, Griffin MDW, Gould AE, Tilley L. Science 376 1074-1079 (2022)
  6. Allosteric Targeting of the Fanconi Anemia Ubiquitin-Conjugating Enzyme Ube2T by Fragment Screening. Morreale FE, Bortoluzzi A, Chaugule VK, Arkinson C, Walden H, Ciulli A. J. Med. Chem. 60 4093-4098 (2017)
  7. Disrupting the Constitutive, Homodimeric Protein-Protein Interface in CK2β Using a Biophysical Fragment-Based Approach. Seetoh WG, Abell C. J. Am. Chem. Soc. 138 14303-14311 (2016)
  8. Optimal allosteric stabilization sites using contact stabilization analysis. Dickson A, Bailey CT, Karanicolas J. J Comput Chem 38 1138-1146 (2017)
  9. Targeting Ligandable Pockets on Plant Homeodomain (PHD) Zinc Finger Domains by a Fragment-Based Approach. Amato A, Lucas X, Bortoluzzi A, Wright D, Ciulli A. ACS Chem. Biol. 13 915-921 (2018)
  10. Three enigmatic BioH isoenzymes are programmed in the early stage of mycobacterial biotin synthesis, an attractive anti-TB drug target. Xu Y, Yang J, Li W, Song S, Shi Y, Wu L, Sun J, Hou M, Wang J, Jia X, Zhang H, Huang M, Lu T, Gan J, Feng Y. PLoS Pathog 18 e1010615 (2022)
  11. A missense mutation in a patient with developmental delay affects the activity and structure of the hexosamine biosynthetic pathway enzyme AGX1. Chen X, Raimi OG, Ferenbach AT, van Aalten DMF. FEBS Lett 595 110-122 (2021)
  12. Identification of Mycobacterium tuberculosis BioA inhibitors by using structure-based virtual screening. Singh S, Khare G, Bahal RK, Ghosh PC, Tyagi AK. Drug Des Devel Ther 12 1065-1079 (2018)
  13. Isothermal Analysis of ThermoFluor Data can readily provide Quantitative Binding Affinities. Bai N, Roder H, Dickson A, Karanicolas J. Sci Rep 9 2650 (2019)
  14. Precipitant-ligand exchange technique reveals the ADP binding mode in Mycobacterium tuberculosis dethiobiotin synthetase. Thompson AP, Wegener KL, Booker GW, Polyak SW, Bruning JB. Acta Crystallogr D Struct Biol 74 965-972 (2018)
  15. The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity. Shi Y, Cao Q, Sun J, Hu X, Su Z, Xu Y, Zhang H, Lan L, Feng Y. PLoS Pathog 19 e1011110 (2023)


Quick links