Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2022 Nov 10

PMID 36355538

Authors

Kirsten McAulay

Alan Bilsland

Marta Bon

Affiliations

Soon will be listed here.

Abstract

Fragment based drug discovery has long been used for the identification of new ligands and interest in targeted covalent inhibitors has continued to grow in recent years, with high profile drugs such as osimertinib and sotorasib gaining FDA approval. It is therefore unsurprising that covalent fragment-based approaches have become popular and have recently led to the identification of novel targets and binding sites, as well as ligands for targets previously thought to be 'undruggable'. Understanding the properties of such covalent fragments is important, and characterizing and/or predicting reactivity can be highly useful. This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.

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References

Tautermann C . Current and Future Challenges in Modern Drug Discovery. Methods Mol Biol. 2020; 2114:1-17. DOI: 10.1007/978-1-0716-0282-9_1. View

Tolmachova K, Moroz Y, Konovets A, Platonov M, Vasylchenko O, Borysko P . (Chlorosulfonyl)benzenesulfonyl Fluorides-Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library. ACS Comb Sci. 2018; 20(11):672-680. DOI: 10.1021/acscombsci.8b00130. View

Vinogradova E, Zhang X, Remillard D, Lazar D, Suciu R, Wang Y . An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells. Cell. 2020; 182(4):1009-1026.e29. PMC: 7775622. DOI: 10.1016/j.cell.2020.07.001. View

Wood D, Lopez-Fernandez J, Knight L, Al-Khawaldeh I, Gai C, Lin S . FragLites-Minimal, Halogenated Fragments Displaying Pharmacophore Doublets. An Efficient Approach to Druggability Assessment and Hit Generation. J Med Chem. 2019; 62(7):3741-3752. DOI: 10.1021/acs.jmedchem.9b00304. View

Tavakoli M, Mood A, Van Vranken D, Baldi P . Quantum Mechanics and Machine Learning Synergies: Graph Attention Neural Networks to Predict Chemical Reactivity. J Chem Inf Model. 2022; 62(9):2121-2132. DOI: 10.1021/acs.jcim.1c01400. View

Barf T, Kaptein A . Irreversible protein kinase inhibitors: balancing the benefits and risks. J Med Chem. 2012; 55(14):6243-62. DOI: 10.1021/jm3003203. View

Cossar P, Wolter M, van Dijck L, Valenti D, Levy L, Ottmann C . Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions. J Am Chem Soc. 2021; 143(22):8454-8464. PMC: 8193639. DOI: 10.1021/jacs.1c03035. View

Zhao Z, Bourne P . Progress with covalent small-molecule kinase inhibitors. Drug Discov Today. 2018; 23(3):727-735. DOI: 10.1016/j.drudis.2018.01.035. View

Abe Y, Shoji M, Nishiya Y, Aiba H, Kishimoto T, Kitaura K . The reaction mechanism of sarcosine oxidase elucidated using FMO and QM/MM methods. Phys Chem Chem Phys. 2017; 19(15):9811-9822. DOI: 10.1039/c6cp08172j. View

10.

Rossetti G, Ossorio M, Rempel S, Kratzel A, Dionellis V, Barriot S . Non-covalent SARS-CoV-2 M inhibitors developed from in silico screen hits. Sci Rep. 2022; 12(1):2505. PMC: 8847420. DOI: 10.1038/s41598-022-06306-4. View

11.

Smith J, Rowley C . Automated computational screening of the thiol reactivity of substituted alkenes. J Comput Aided Mol Des. 2015; 29(8):725-35. DOI: 10.1007/s10822-015-9857-0. View

12.

Dubiella C, Pinch B, Koikawa K, Zaidman D, Poon E, Manz T . Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo. Nat Chem Biol. 2021; 17(9):954-963. PMC: 9119696. DOI: 10.1038/s41589-021-00786-7. View

13.

Jhoti H, Williams G, Rees D, Murray C . The 'rule of three' for fragment-based drug discovery: where are we now?. Nat Rev Drug Discov. 2013; 12(8):644-5. DOI: 10.1038/nrd3926-c1. View

14.

Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y . Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach. J Med Chem. 2020; 63(13):7052-7065. DOI: 10.1021/acs.jmedchem.0c00372. View

15.

Roy Chowdhury S, Kennedy S, Zhu K, Mishra R, Chuong P, Nguyen A . Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments. Bioorg Med Chem Lett. 2018; 29(1):36-39. PMC: 6319256. DOI: 10.1016/j.bmcl.2018.11.019. View

16.

Wu G, Zhao T, Kang D, Zhang J, Song Y, Namasivayam V . Overview of Recent Strategic Advances in Medicinal Chemistry. J Med Chem. 2019; 62(21):9375-9414. DOI: 10.1021/acs.jmedchem.9b00359. View

17.

Jost C, Nitsche C, Scholz T, Roux L, Klein C . Promiscuity and selectivity in covalent enzyme inhibition: a systematic study of electrophilic fragments. J Med Chem. 2014; 57(18):7590-9. DOI: 10.1021/jm5006918. View

18.

Wen C, Yan X, Gu Q, Du J, Wu D, Lu Y . Systematic Studies on the Protocol and Criteria for Selecting a Covalent Docking Tool. Molecules. 2019; 24(11). PMC: 6600387. DOI: 10.3390/molecules24112183. View

19.

Keeley A, Petri L, Abranyi-Balogh P, Keseru G . Covalent fragment libraries in drug discovery. Drug Discov Today. 2020; 25(6):983-996. DOI: 10.1016/j.drudis.2020.03.016. View

20.

Olp M, Sprague D, Goetz C, Kathman S, Wynia-Smith S, Shishodia S . Covalent-Fragment Screening of BRD4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites. ACS Chem Biol. 2020; 15(4):1036-1049. PMC: 7271629. DOI: 10.1021/acschembio.0c00058. View