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De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments.

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Urich R, Wishart G, Kiczun M, Richters A, Tidten-Luksch N, Rauh D, Sherborne B, Wyatt PG, Brenk R
OpenAccess logo ACS Chem Biol 8 1044-52 (2013)
Cited: 18 times
EuropePMC logo PMID: 23534475

Abstract

Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.

Reviews - 4fic mentioned but not cited (1)

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Articles - 4fic mentioned but not cited (1)

  1. De novo design of protein kinase inhibitors by in silico identification of hinge region-binding fragments. Urich R, Wishart G, Kiczun M, Richters A, Tidten-Luksch N, Rauh D, Sherborne B, Wyatt PG, Brenk R. ACS Chem Biol 8 1044-1052 (2013)


Reviews citing this publication (4)

  1. Aminoazole-Based Diversity-Oriented Synthesis of Heterocycles. Murlykina MV, Morozova AD, Zviagin IM, Sakhno YI, Desenko SM, Chebanov VA. Front Chem 6 527 (2018)
  2. Panel docking of small-molecule libraries - Prospects to improve efficiency of lead compound discovery. Sarnpitak P, Mujumdar P, Taylor P, Cross M, Coster MJ, Gorse AD, Krasavin M, Hofmann A. Biotechnol Adv 33 941-947 (2015)
  3. Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study. Atkinson EL, Iegre J, Brear PD, Zhabina EA, Hyvönen M, Spring DR. Molecules 26 1977 (2021)
  4. DOCKSTRING: Easy Molecular Docking Yields Better Benchmarks for Ligand Design. García-Ortegón M, Simm GNC, Tripp AJ, Hernández-Lobato JM, Bender A, Bacallado S. J Chem Inf Model 62 3486-3502 (2022)

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  1. Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity. Vanaerschot M, Murithi JM, Pasaje CFA, Ghidelli-Disse S, Dwomoh L, Bird M, Spottiswoode N, Mittal N, Arendse LB, Owen ES, Wicht KJ, Siciliano G, Bösche M, Yeo T, Kumar TRS, Mok S, Carpenter EF, Giddins MJ, Sanz O, Ottilie S, Alano P, Chibale K, Llinás M, Uhlemann AC, Delves M, Tobin AB, Doerig C, Winzeler EA, Lee MCS, Niles JC, Fidock DA. Cell Chem Biol 27 806-816.e8 (2020)
  2. The Groebke-Blackburn-Bienaymé Reaction. Boltjes A, Dömling A. Eur J Chem 2019 7007-7049 (2019)
  3. Benzobisthiazoles Represent a Novel Scaffold for Kinase Inhibitors of CLK Family Members. Prak K, Kriston-Vizi J, Chan AW, Luft C, Costa JR, Pengo N, Ketteler R. Biochemistry 55 608-617 (2016)
  4. Chalcone-based Selective Inhibitors of a C4 Plant Key Enzyme as Novel Potential Herbicides. Nguyen GT, Erlenkamp G, Jäck O, Küberl A, Bott M, Fiorani F, Gohlke H, Groth G. Sci Rep 6 27333 (2016)
  5. Discovery of a novel kinase hinge binder fragment by dynamic undocking. Rachman M, Bajusz D, Hetényi A, Scarpino A, Merő B, Egyed A, Buday L, Barril X, Keserű GM. RSC Med Chem 11 552-558 (2020)
  6. Fragment-based strategy for structural optimization in combination with 3D-QSAR. Yuan H, Tai W, Hu S, Liu H, Zhang Y, Yao S, Ran T, Lu S, Ke Z, Xiong X, Xu J, Chen Y, Lu T. J Comput Aided Mol Des 27 897-915 (2013)
  7. Ligand-Based Pharmacophore Screening Strategy: a Pragmatic Approach for Targeting HER Proteins. James N, Ramanathan K. Appl Biochem Biotechnol 186 85-108 (2018)
  8. Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts. Oebbeke M, Siefker C, Wagner B, Heine A, Klebe G. Angew Chem Int Ed Engl 60 252-258 (2021)
  9. Data driven polypharmacological drug design for lung cancer: analyses for targeting ALK, MET, and EGFR. Narayanan D, Gani OABSM, Gruber FXE, Engh RA. J Cheminform 9 43 (2017)
  10. Identification of type I and type II inhibitors of c-Yes kinase using in silico and experimental techniques. Ramakrishnan C, Mary Thangakani A, Velmurugan D, Anantha Krishnan D, Sekijima M, Akiyama Y, Gromiha MM. J Biomol Struct Dyn 36 1566-1576 (2018)
  11. How Ligands Interact with the Kinase Hinge. Zhao Z, Bourne PE. ACS Med Chem Lett 14 1503-1508 (2023)
  12. Synthesis, Structure and Cytotoxicity Testing of Novel 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives. Balewski Ł, Sączewski F, Bednarski PJ, Wolff L, Nadworska A, Gdaniec M, Kornicka A. Molecules 25 E5924 (2020)


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