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Discovery of a potent CDK2 inhibitor with a novel binding mode, using virtual screening and initial, structure-guided lead scoping.

Richardson CM, Nunns CL, Williamson DS, Parratt MJ, Dokurno P, Howes R, Borgognoni J, Drysdale MJ, Finch H, Hubbard RE, Jackson PS, Kierstan P, Lentzen G, Moore JD, Murray JB, Simmonite H, Surgenor AE, Torrance CJ
Bioorg Med Chem Lett 17 3880-5 (2007)
Related entries: 2uzb, 2uzd, 2uze, 2uzn, 2uzo, 2v0d

Cited: 20 times
EuropePMC logo PMID: 17570665

Abstract

Virtual screening against a pCDK2/cyclin A crystal structure led to the identification of a potent and novel CDK2 inhibitor, which exhibited an unusual mode of interaction with the kinase binding motif. With the aid of X-ray crystallography and modelling, a medicinal chemistry strategy was implemented to probe the interactions seen in the crystal structure and to establish SAR. A fragment-based approach was also considered but a different, more conventional, binding mode was observed. Compound selectivity against GSK-3beta was improved using a rational design strategy, with crystallographic verification of the CDK2 binding mode.

Articles - 2uzl mentioned but not cited (1)

  1. Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases. Ma Z, Huang SY, Cheng F, Zou X. J Phys Chem B 125 2288-2298 (2021)


Reviews citing this publication (4)

  1. Application of NMR and molecular docking in structure-based drug discovery. Stark JL, Powers R. Top Curr Chem 326 1-34 (2012)
  2. Structure-based drug discovery and protein targets in the CNS. Hubbard RE. Neuropharmacology 60 7-23 (2011)
  3. Recent advances on CDK inhibitors: An insight by means of in silico methods. Tutone M, Almerico AM. Eur J Med Chem 142 300-315 (2017)
  4. Recent advances in synthetic strategies and SAR of thiazolidin-4-one containing molecules in cancer therapeutics. Sharma A, Sharma D, Saini N, Sharma SV, Thakur VK, Goyal RK, Sharma PC. Cancer Metastasis Rev 42 847-889 (2023)

Articles citing this publication (15)

  1. High-throughput kinase profiling: a more efficient approach toward the discovery of new kinase inhibitors. Miduturu CV, Deng X, Kwiatkowski N, Yang W, Brault L, Filippakopoulos P, Chung E, Yang Q, Schwaller J, Knapp S, King RW, Lee JD, Herrgard S, Zarrinkar P, Gray NS. Chem. Biol. 18 868-879 (2011)
  2. Lessons for fragment library design: analysis of output from multiple screening campaigns. Chen IJ, Hubbard RE. J. Comput. Aided Mol. Des. 23 603-620 (2009)
  3. High-throughput and in silico screenings in drug discovery. Phatak SS, Stephan CC, Cavasotto CN. Expert Opin Drug Discov 4 947-959 (2009)
  4. Protein-Ligand interaction studies on 2, 4, 6- trisubstituted triazine derivatives as anti-malarial DHFR agents using AutoDock. Adinarayana KP, Devi RK. Bioinformation 6 74-77 (2011)
  5. Chemical space sampling by different scoring functions and crystal structures. Brooijmans N, Humblet C. J. Comput. Aided Mol. Des. 24 433-447 (2010)
  6. Thiazolidinedione-based PI3Kα inhibitors: an analysis of biochemical and virtual screening methods. Pinson JA, Schmidt-Kittler O, Zhu J, Jennings IG, Kinzler KW, Vogelstein B, Chalmers DK, Thompson PE. ChemMedChem 6 514-522 (2011)
  7. Design, synthesis and biological evaluation of 5-benzylidene-2-iminothiazolidin-4-ones as selective GSK-3β inhibitors. Arfeen M, Bhagat S, Patel R, Prasad S, Roy I, Chakraborti AK, Bharatam PV. Eur J Med Chem 121 727-736 (2016)
  8. Role of interactions and volume variation in discriminating active and inactive forms of cyclin-dependent kinase-2 inhibitor complexes. Saranya N, Selvaraj S. Chem Biol Drug Des 78 361-369 (2011)
  9. Biased retrieval of chemical series in receptor-based virtual screening. Brooijmans N, Cross JB, Humblet C. J. Comput. Aided Mol. Des. 24 1053-1062 (2010)
  10. Novel 4-(4-substituted-thiazol-2-ylamino)-N-(pyridin-2-yl)-benzenesulfonamides as cytotoxic and radiosensitizing agents. Ghorab MM, Ragab FA, Heiba HI, Agha HM, Nissan YM. Arch. Pharm. Res. 35 59-68 (2012)
  11. Structure-guided microbial targeting of antistaphylococcal prodrugs. Miller JJ, Shah IT, Hatten J, Barekatain Y, Mueller EA, Moustafa AM, Edwards RL, Dowd CS, Hoops GC, Johnson RJ, Planet PJ, Muller FL, Jez JM, Odom John AR. Elife 10 e66657 (2021)
  12. Anti-cancer potency by induced apoptosis by molecular docking P53, caspase, cyclin D1, cytotoxicity analysis and phagocytosis activity of trisindoline 1,3 and 4. Nurhayati APD, Rihandoko A, Fadlan A, Ghaissani SS, Jadid N, Setiawan E. Saudi Pharm J 30 1345-1359 (2022)
  13. Crystal structure of 4-bromo-N-(propyl-carbamo-yl)benzene-sulfonamide. Bookwala M, Patel S, Flaherty PT, Wildfong PLD. Acta Crystallogr E Crystallogr Commun 78 485-489 (2022)
  14. Identification of novel CDK2 inhibitors by a multistage virtual screening method based on SVM, pharmacophore and docking model. Liang JW, Wang MY, Wang S, Li SL, Li WQ, Meng FH. J Enzyme Inhib Med Chem 35 235-244 (2020)
  15. Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking. Fatahala SS, Sayed AI, Mahgoub S, Taha H, El-Sayed MK, El-Shehry MF, Awad SM, Abd El-Hameed RH. Int J Mol Sci 22 11957 (2021)


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