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High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery.

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Craven GB, Affron DP, Allen CE, Matthies S, Greener JG, Morgan RML, Tate EW, Armstrong A, Mann DJ
OpenAccess logo Angew Chem Int Ed Engl 57 5257-5261 (2018)
Related entries: 5osj, 5osm

Cited: 23 times
EuropePMC logo PMID: 29480525

Abstract

Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.

Articles - 5oo0 mentioned but not cited (3)

  1. High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery. Craven GB, Affron DP, Allen CE, Matthies S, Greener JG, Morgan RML, Tate EW, Armstrong A, Mann DJ. Angew Chem Int Ed Engl 57 5257-5261 (2018)
  2. Exploring ligand binding pathways on proteins using hypersound-accelerated molecular dynamics. Araki M, Matsumoto S, Bekker GJ, Isaka Y, Sagae Y, Kamiya N, Okuno Y. Nat Commun 12 2793 (2021)
  3. Systematic Analysis of Covalent and Allosteric Protein Kinase Inhibitors. Xerxa E, Laufkötter O, Bajorath J. Molecules 28 5805 (2023)


Reviews citing this publication (5)

  1. The design and development of covalent protein-protein interaction inhibitors for cancer treatment. Cheng SS, Yang GJ, Wang W, Leung CH, Ma DL. J Hematol Oncol 13 26 (2020)
  2. Fragment-based covalent ligand discovery. Lu W, Kostic M, Zhang T, Che J, Patricelli MP, Jones LH, Chouchani ET, Gray NS. RSC Chem Biol 2 354-367 (2021)
  3. Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery. McAulay K, Bilsland A, Bon M. Pharmaceuticals (Basel) 15 1366 (2022)
  4. Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†. Faber EB, Wang N, Georg GI. Biol Reprod 103 357-367 (2020)
  5. Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices. Oyedele AK, Ogunlana AT, Boyenle ID, Adeyemi AO, Rita TO, Adelusi TI, Abdul-Hammed M, Elegbeleye OE, Odunitan TT. Mol Divers 27 1879-1903 (2023)

Articles citing this publication (15)

  1. Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening. Resnick E, Bradley A, Gan J, Douangamath A, Krojer T, Sethi R, Geurink PP, Aimon A, Amitai G, Bellini D, Bennett J, Fairhead M, Fedorov O, Gabizon R, Gan J, Guo J, Plotnikov A, Reznik N, Ruda GF, Díaz-Sáez L, Straub VM, Straub VM, Szommer T, Velupillai S, Zaidman D, Zhang Y, Coker AR, Dowson CG, Barr HM, Wang C, Huber KVM, Brennan PE, Ovaa H, von Delft F, London N. J Am Chem Soc 141 8951-8968 (2019)
  2. Characterising covalent warhead reactivity. Martin JS, MacKenzie CJ, Fletcher D, Gilbert IH. Bioorg Med Chem 27 2066-2074 (2019)
  3. An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor. Zaidman D, Gehrtz P, Filep M, Fearon D, Gabizon R, Douangamath A, Prilusky J, Duberstein S, Cohen G, Owen CD, Resnick E, Strain-Damerell C, Lukacik P, Covid-Moonshot Consortium, Barr H, Walsh MA, von Delft F, London N. Cell Chem Biol 28 1795-1806.e5 (2021)
  4. 10 years into the resurgence of covalent drugs. De Vita E. Future Med Chem 13 193-210 (2021)
  5. Development of CDK2 and CDK5 Dual Degrader TMX-2172. Teng M, Jiang J, He Z, Kwiatkowski NP, Donovan KA, Mills CE, Victor C, Hatcher JM, Fischer ES, Sorger PK, Zhang T, Gray NS. Angew Chem Int Ed Engl 59 13865-13870 (2020)
  6. Embracing the Diversity of Halogen Bonding Motifs in Fragment-Based Drug Discovery-Construction of a Diversity-Optimized Halogen-Enriched Fragment Library. Heidrich J, Sperl LE, Boeckler FM. Front Chem 7 9 (2019)
  7. In silico screening-based discovery of novel covalent inhibitors of the SARS-CoV-2 3CL protease. Xiong M, Nie T, Shao Q, Li M, Su H, Xu Y. Eur J Med Chem 231 114130 (2022)
  8. Multicomponent reaction-derived covalent inhibitor space. Sutanto F, Shaabani S, Neochoritis CG, Zarganes-Tzitzikas T, Patil P, Ghonchepour E, Dömling A. Sci Adv 7 eabd9307 (2021)
  9. Functionalized Scout Fragments for Site-Specific Covalent Ligand Discovery and Optimization. Crowley VM, Thielert M, Cravatt BF. ACS Cent Sci 7 613-623 (2021)
  10. Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering (qIT). Craven GB, Affron DP, Kösel T, Wong TLM, Jukes ZH, Liu CT, Morgan RML, Armstrong A, Mann DJ. Chembiochem 21 3417-3422 (2020)
  11. Identification of the first structurally validated covalent ligands of the small GTPase RAB27A. Jamshidiha M, Lanyon-Hogg T, Sutherell CL, Craven GB, Tersa M, De Vita E, Brustur D, Pérez-Dorado I, Hassan S, Petracca R, Morgan RM, Sanz-Hernández M, Norman JC, Armstrong A, Mann DJ, Cota E, Tate EW. RSC Med Chem 13 150-155 (2022)
  12. Emerging approaches to CDK inhibitor development, a structural perspective. Hope I, Endicott JA, Watt JE. RSC Chem Biol 4 146-164 (2023)
  13. Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease. Qin B, Craven GB, Hou P, Chesti J, Lu X, Child ES, Morgan RML, Niu W, Zhao L, Armstrong A, Mann DJ, Cui S. Acta Pharm Sin B 12 3924-3933 (2022)
  14. Cyclin D-CDK4 Disulfide Bond Attenuates Pulmonary Vascular Cell Proliferation. Knight H, Abis G, Kaur M, Green HLH, Krasemann S, Hartmann K, Lynham S, Clark J, Zhao L, Ruppert C, Weiss A, Schermuly RT, Eaton P, Rudyk O. Circ Res 133 966-988 (2023)
  15. Quantitative Irreversible Tethering (qIT) for Target-directed Covalent Fragment Screening. Craven GB, Armstrong A, Mann DJ. Bio Protoc 10 e3855 (2020)


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