Skip to content
2000
Volume 29, Issue 18
  • ISSN: 1385-2728
  • E-ISSN: 1875-5348

Abstract

Covalent inhibitor drugs or targeted covalent inhibitors (TCIs) are a type of drug category that interact with their target by covalent bond formation. They represent a unique category having desired properties such as high potency and longer duration of action, making them an attractive opportunity to pursue by researchers in drug discovery. In history, covalent inhibitors were often discovered serendipitously ( aspirin and penicillin). However, modern times have witnessed numerous cases of rational design of these drugs, which has caused their rise to occupy a significant fraction of marketed drugs (over 30%). Here, we have given an overview of the discovery process of covalent inhibitors, including target identification/validation, warhead selection and optimization, linker design and conjugation and the role of computational tools in covalent inhibitors. To conclude, the challenges in this field and future directions to foresee are discussed. The objective of this article is to provide a summary of the general development process of covalent inhibitors as well as prospects or research gaps awaiting to be solved to overcome the challenges that hinder the discovery of covalent drugs.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/coc/10.2174/0113852728361926250123092017
2025-02-17
2025-09-27

  • From This Site

    /content/journals/coc/10.2174/0113852728361926250123092017
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. McWhirterC. Kinetic mechanisms of covalent inhibition.The Design of Covalent-Based Inhibitors.Academic Press202113110.1016/bs.armc.2020.11.001
     [Google Scholar]
  2. SutantoF. KonstantinidouM. DömlingA. Covalent inhibitors: A rational approach to drug discovery.RSC med. chem.202011887688410.1039/D0MD00154F 33479682
     [Google Scholar]
  3. SinghJ. The ascension of targeted covalent inhibitors.J. Med. Chem.20226585886590110.1021/acs.jmedchem.1c02134 35439421
     [Google Scholar]
  4. The rise of covalent inhibitors in strategic therapeutic design.2023https://www.cas.org/resources/cas-insights/rise-covalent-inhibitors-strategic-therapeutic-design
  5. Advantages and disadvantages of covalent inhibitors.2023https://encyclopedia.pub/entry/43976
  6. LuD. YuX. LinH. ChengR. MonroyE.Y. QiX. WangM.C. WangJ. Applications of covalent chemistry in targeted protein degradation.Chem. Soc. Rev.202251229243926110.1039/D2CS00362G 36285735
     [Google Scholar]
  7. BarraganA.M. GhabyK. PondM.P. RouxB. Computational investigation of the covalent inhibition mechanism of Bruton’s tyrosine kinase by Ibrutinib.J. Chem. Inf. Model.20246483488350210.1021/acs.jcim.4c00023 38546820
     [Google Scholar]
  8. VoiceA.T. TresadernG. TwidaleR.M. van VlijmenH. MulhollandA.J. Mechanism of covalent binding of ibrutinib to Bruton’s tyrosine kinase revealed by QM/MM calculations.Chem. Sci. (Camb.)202112155511551610.1039/D0SC06122K 33995994
     [Google Scholar]
  9. MehtaN.V. DeganiM.S. The expanding repertoire of covalent warheads for drug discovery.Drug Discov. Today2023281210379910.1016/j.drudis.2023.103799 37839776
     [Google Scholar]
  10. MondalD. WarshelA. Exploring the mechanism of covalent inhibition: Simulating the binding free energy of α-ketoamide inhibitors of the main protease of SARS-CoV-2.Biochemistry202059484601460810.1021/acs.biochem.0c00782 33205654
     [Google Scholar]
  11. MeissnerF. Geddes-McAlisterJ. MannM. BantscheffM. The emerging role of mass spectrometry-based proteomics in drug discovery.Nat. Rev. Drug Discov.202221963765410.1038/s41573‑022‑00409‑3 35351998
     [Google Scholar]
  12. LonsdaleR. BurgessJ. ColcloughN. DaviesN.L. LenzE.M. OrtonA.L. WardR.A. Expanding the armory: Predicting and tuning covalent warhead reactivity.J. Chem. Inf. Model.201757123124313710.1021/acs.jcim.7b00553 29131621
     [Google Scholar]
  13. ZhangG. ZhangJ. GaoY. LiY. LiY. Strategies for targeting undruggable targets.Expert Opin. Drug Discov.2022171556910.1080/17460441.2021.1969359 34455870
     [Google Scholar]
  14. DuH. GaoJ. WengG. DingJ. ChaiX. PangJ. KangY. LiD. CaoD. HouT. CovalentInDB: A comprehensive database facilitating the discovery of covalent inhibitors.Nucleic Acids Res.202149D1D1122D112910.1093/nar/gkaa876 33068433
     [Google Scholar]
  15. GuoY. shuaiW. TongA. WangY. Advanced technologies for screening and identifying covalent inhibitors.Trends Analyt. Chem.202417811783310.1016/j.trac.2024.117833
     [Google Scholar]
  16. ZhengL. LiY. WuD. XiaoH. ZhengS. WangG. SunQ. Development of covalent inhibitors: Principle, design, and application in cancer.MedComm Oncol.202324e5610.1002/mog2.56
     [Google Scholar]
  17. KrishnaR. RiouxN. Developing targeted covalent inhibitor drugs: 3 key considerations,2021https://www.certara.com/blog/developing-targeted-covalent-inhibitor-drugs-3-key-considerations/
  18. JonesL.H. Design of next-generation covalent inhibitors: Targeting residues beyond cysteine.The Design of Covalent-Based Inhibitors.Academic Press20219513410.1016/bs.armc.2020.10.001
     [Google Scholar]
  19. CsorbaN. Ábrányi-BaloghP. KeserűG.M. Covalent fragment approaches targeting non-cysteine residues.Trends Pharmacol. Sci.2023441180281610.1016/j.tips.2023.08.014 37770315
     [Google Scholar]
  20. De CescoS. KurianJ. DufresneC. MittermaierA.K. MoitessierN. Covalent inhibitors design and discovery.Eur. J. Med. Chem.20171389611410.1016/j.ejmech.2017.06.019 28651155
     [Google Scholar]
  21. RaoufY.S. Covalent inhibitors: To infinity and beyond.J. Med. Chem.20246713105131051610.1021/acs.jmedchem.4c01308 38913822
     [Google Scholar]
  22. BhattT.K. NimeshS. The Design and Development of Novel Drugs and Vaccines: Principles and Protocols.Academic Press2021
     [Google Scholar]
  23. DaiL. LiZ. ChenD. JiaL. GuoJ. ZhaoT. NordlundP. Target identification and validation of natural products with label-free methodology: A critical review from 2005 to 2020.Pharmacol. Ther.202021610769010.1016/j.pharmthera.2020.107690 32980441
     [Google Scholar]
  24. RousseauxC.G. BrackenW.M. Overview of Drug Development.Haschek and Rousseaux’s Handbook of Toxicologic Pathology 3rd ed;s HaschekW.M. RousseauxC.G. WalligM.A. Academic Press: Boston201364768510.1016/B978‑0‑12‑415759‑0.00021‑2
     [Google Scholar]
  25. PéczkaN. OrgovánZ. Ábrányi-BaloghP. KeserűG.M. Electrophilic warheads in covalent drug discovery: An overview.Expert Opin. Drug Discov.202217441342210.1080/17460441.2022.2034783 35129005
     [Google Scholar]
  26. MartinJ.S. MacKenzieC.J. FletcherD. GilbertI.H. Characterising covalent warhead reactivity.Bioorg. Med. Chem.201927102066207410.1016/j.bmc.2019.04.002 30975501
     [Google Scholar]
  27. ShindoN. OjidaA. Recent progress in covalent warheads for in vivo targeting of endogenous proteins.Bioorg. Med. Chem.20214711638610.1016/j.bmc.2021.116386 34509863
     [Google Scholar]
  28. GehringerM. LauferS.A. Emerging and re-emerging warheads for targeted covalent inhibitors: Applications in medicinal chemistry and chemical biology.J. Med. Chem.201962125673572410.1021/acs.jmedchem.8b01153 30565923
     [Google Scholar]
  29. HillebrandL. LiangX.J. SerafimR.A.M. GehringerM. Emerging and re-emerging warheads for targeted covalent inhibitors: An update.J. Med. Chem.202467107668775810.1021/acs.jmedchem.3c01825 38711345
     [Google Scholar]
  30. BaillieT.A. Targeted covalent inhibitors for drug design.Angew. Chem. Int. Ed.20165543134081342110.1002/anie.201601091 27539547
     [Google Scholar]
  31. MauraisA.J. WeerapanaE. Reactive-cysteine profiling for drug discovery.Curr. Opin. Chem. Biol.201950293610.1016/j.cbpa.2019.02.010 30897495
     [Google Scholar]
  32. YverA. Osimertinib (AZD9291): A science-driven, collaborative approach to rapid drug design and development.Ann. Oncol.20162761165117010.1093/annonc/mdw129 26961148
     [Google Scholar]
  33. LuX. SmaillJ.B. PattersonA.V. DingK. Discovery of cysteine-targeting covalent protein kinase inhibitors.J. Med. Chem.2022651588310.1021/acs.jmedchem.1c01719 34962782
     [Google Scholar]
  34. DanilackA.D. DicksonC.J. SoyluC. FortunatoM. RoddeS. MunklerH. HornakV. DucaJ.S. Reactivities of acrylamide warheads toward cysteine targets: A QM/ML approach to covalent inhibitor design.J. Comput. Aided Mol. Des.20243812110.1007/s10822‑024‑00560‑6 38693331
     [Google Scholar]
  35. HuangF. HanX. XiaoX. ZhouJ. Covalent warheads targeting cysteine residue: The promising approach in drug development.Molecules20222722772810.3390/molecules27227728 36431829
     [Google Scholar]
  36. LiX. SongY. Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review.Eur. J. Med. Chem.202326011577210.1016/j.ejmech.2023.115772 37659195
     [Google Scholar]
  37. ChenD. GuoD. YanZ. ZhaoY. Allenamide as a bioisostere of acrylamide in the design and synthesis of targeted covalent inhibitors.MedChemComm20189224425310.1039/C7MD00571G 30108918
     [Google Scholar]
  38. McAulayK. HoytE.A. ThomasM. SchimplM. BodnarchukM.S. LewisH.J. BarrattD. BhavsarD. RobinsonD.M. DeeryM.J. OggD.J. BernardesG.J.L. WardR.A. WaringM.J. KettleJ.G. Alkynyl benzoxazines and dihydroquinazolines as cysteine targeting covalent warheads and their application in identification of selective irreversible kinase inhibitors.J. Am. Chem. Soc.202014223103581037210.1021/jacs.9b13391 32412754
     [Google Scholar]
  39. HackerS.M. BackusK.M. LazearM.R. ForliS. CorreiaB.E. CravattB.F. Global profiling of lysine reactivity and ligandability in the human proteome.Nat. Chem.20179121181119010.1038/nchem.2826 29168484
     [Google Scholar]
  40. BollL.B. RainesR.T. Context‐dependence of the reactivity of cysteine and lysine residues.ChemBioChem20222314e20220025810.1002/cbic.202200258 35527228
     [Google Scholar]
  41. RamaziS. ZahiriJ. Post-translational modifications in proteins: Resources, tools and prediction methods.Database (Oxford)20212021baab01210.1093/database/baab012 33826699
     [Google Scholar]
  42. KawanoM. MurakawaS. HigashiguchiK. MatsudaK. TamuraT. HamachiI. Lysine-L N -Acyl- N -aryl Sulfonamide Warheads: Improved reaction properties and application in the covalent inhibition of an ibrutinib-resistant BTK Mutant.J. Am. Chem. Soc.202314548262022621210.1021/jacs.3c08740 37987622
     [Google Scholar]
  43. PettingerJ. JonesK. CheesemanM.D. Lysine‐targeting covalent inhibitors.Angew. Chem. Int. Ed.20175648152001520910.1002/anie.201707630 28853194
     [Google Scholar]
  44. UdompholkulP. BaggioC. GambiniL. AlboreggiaG. PellecchiaM. Lysine covalent antagonists of melanoma inhibitors of apoptosis protein.J. Med. Chem.20216421161471615810.1021/acs.jmedchem.1c01459 34705456
     [Google Scholar]
  45. GoinsC.M. SudasingheT.D. LiuX. WangY. O’DohertyG.A. RonningD.R. Characterization of tetrahydrolipstatin and stereoderivatives on the inhibition of essential Mycobacterium tuberculosis lipid esterases.Biochemistry201857162383239310.1021/acs.biochem.8b00152 29601187
     [Google Scholar]
  46. WangY.H. ZhangF. DiaoH. WuR. Covalent inhibition mechanism of antidiabetic drugs—Vildagliptin vs Saxagliptin.ACS Catal.2019932292230210.1021/acscatal.8b05051
     [Google Scholar]
  47. FallahA. MohanazadehF. SafaviM. Design, synthesis, and in vitro evaluation of novel 1,3,4-oxadiazolecarbamothioate derivatives of Rivastigmine as selective inhibitors of BuChE.Med. Chem. Res.202029334135510.1007/s00044‑019‑02475‑6
     [Google Scholar]
  48. RayS. MurkinA.S. New electrophiles and strategies for mechanism-based and targeted covalent inhibitor design.Biochemistry201958525234524410.1021/acs.biochem.9b00293 30990686
     [Google Scholar]
  49. RuddrarajuK.V. ZhangZ.Y. Covalent inhibition of protein tyrosine phosphatases.Mol. Biosyst.20171371257127910.1039/C7MB00151G 28534914
     [Google Scholar]
  50. EdgcombS.P. MurphyK.P. Variability in the pKa of histidine side‐chains correlates with burial within proteins.Proteins20024911610.1002/prot.10177 12211010
     [Google Scholar]
  51. CheJ. JonesL.H. Covalent drugs targeting histidine: An unexploited opportunity?RSC Med. Chem.202213101121112610.1039/D2MD00258B 36325394
     [Google Scholar]
  52. CompainG. MonsarratC. BlagojevicJ. BrilletK. DumasP. HammannP. KuhnL. MartielI. EngilbergeS. OliéricV. WolffP. BurnoufD.Y. WagnerJ. GuichardG. Peptide-based covalent inhibitors bearing mild electrophiles to target a conserved his residue of the bacterial sliding clamp.JACS Au20244243244010.1021/jacsau.3c00572 38425897
     [Google Scholar]
  53. HeinrichT. ZenkeF.T. BomkeJ. GuneraJ. WegenerA. Friese-HamimM. HewittP. Methionine aminopeptidases.Metalloenzymes. SupuranC.T. DonaldW.A. Academic Press202434337310.1016/B978‑0‑12‑823974‑2.00023‑1
     [Google Scholar]
  54. AnscombeE. MeschiniE. Mora-VidalR. MartinM.P. StauntonD. GeitmannM. DanielsonU.H. StanleyW.A. WangL.Z. ReuillonT. GoldingB.T. CanoC. NewellD.R. NobleM.E.M. WedgeS.R. EndicottJ.A. GriffinR.J. Identification and characterization of an irreversible inhibitor of CDK2.Chem. Biol.20152291159116410.1016/j.chembiol.2015.07.018 26320860
     [Google Scholar]
  55. ThomasR.P. GrantE.K. DickinsonE.R. ZappacostaF. EdwardsL.J. HannM.M. HouseD. TomkinsonN.C.O. BushJ. T Reactive fragments targeting carboxylate residues employing direct to biology, high-throughput chemistry.RSC Med. Chem.1467167910.1039/D2MD00453D
     [Google Scholar]
  56. OfmanT.P. van der MarelG.A. CodéeJ.D.C. OverkleeftH.S. Design and synthesis of exocyclic cyclitol aziridines as potential mechanism‐based glycosidase inactivators.Eur. J. Org. Chem.20232616e20230018610.1002/ejoc.202300186
     [Google Scholar]
  57. SilvaM.P. SaraivaL. PintoM. SousaM.E. Boronic acids and their derivatives in medicinal chemistry: Synthesis and biological applications.Molecules20202518432310.3390/molecules25184323 32967170
     [Google Scholar]
  58. CheA. Installing the acrylamide warheads in the FDA-approved covalent drugs.2023https://medium.com/@allen-che/acryloylamide-warhead-insta-llation-in-fda-approved-covalent-inhibitors-9402b4a26dfd
  59. KlugeA.F. PetterR.C. Acylating drugs: Redesigning natural covalent inhibitors.Curr. Opin. Chem. Biol.201014342142710.1016/j.cbpa.2010.03.035 20457000
     [Google Scholar]
  60. SandanayakaV. PrashadA. Resistance to β-lactam antibiotics: Structure and mechanism based design of β-lactamase inhibitors.Curr. Med. Chem.20029121145116510.2174/0929867023370031 12052169
     [Google Scholar]
  61. BonattoV. LameiroR.F. RochoF.R. LameiraJ. LeitãoA. MontanariC.A. Nitriles: An attractive approach to the development of covalent inhibitors.RSC Med. Chem.202314220121710.1039/D2MD00204C
     [Google Scholar]
  62. DuS. HuX. LindsleyC.W. ZhanP. New Applications of sulfonyl fluorides: A microcosm of the deep integration of chemistry and biology in drug design.J. Med. Chem.20246719169251692710.1021/acs.jmedchem.4c02112 39315939
     [Google Scholar]
  63. GambiniL. UdompholkulP. SalemA.F. BaggioC. PellecchiaM. Stability and cell permeability of sulfonyl fluorides in the design of lys‐covalent antagonists of protein‐protein interactions.ChemMedChem202015222176218410.1002/cmdc.202000355 32790900
     [Google Scholar]
  64. NarayananA. JonesL.H. Sulfonyl fluorides as privileged warheads in chemical biology.Chem. Sci. (Camb.)2015652650265910.1039/C5SC00408J 28706662
     [Google Scholar]
  65. PlesciaJ. MoitessierN. Design and discovery of boronic acid drugs.Eur. J. Med. Chem.202019511227010.1016/j.ejmech.2020.112270 32302879
     [Google Scholar]
  66. FaridoonR. NgR. ZhangG. LiJ.J. An update on the discovery and development of reversible covalent inhibitors.Med. Chem. Res.20233261039106210.1007/s00044‑023‑03065‑3 37305209
     [Google Scholar]
  67. GomesA.R. VarelaC.L. Tavares-da-SilvaE.J. RoleiraF.M.F. Epoxide containing molecules: A good or a bad drug design approach.Eur. J. Med. Chem.202020111232710.1016/j.ejmech.2020.112327 32526552
     [Google Scholar]
  68. SchieferI.T. TapadarS. LitoshV. SiklosM. ScismR. WijewickramaG.T. ChandrasenaE.P. SinhaV. TavassoliE. BrunsteinerM. Fa’M. ArancioO. PetukhovP. ThatcherG.R.J. Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors.J. Med. Chem.201356156054606810.1021/jm4006719 23834438
     [Google Scholar]
  69. MorisseauC. HammockB.D. Epoxide hydrolases: Mechanisms, inhibitor designs, and biological roles.Annu. Rev. Pharmacol. Toxicol.20054531133310.1146/annurev.pharmtox.45.120403.095920
     [Google Scholar]
  70. IsmailF.M.D. LevitskyD.O. DembitskyV.M. Aziridine alkaloids as potential therapeutic agents.Eur. J. Med. Chem.20094493373338710.1016/j.ejmech.2009.05.013 19540628
     [Google Scholar]
  71. AdamsB.T. NiccoliS. ChowdhuryM.A. EsarikA.N. LeesL.J. RempelB.P. PhenixC.P. N-Alkylated aziridines are easily-prepared, potent, specific and cell-permeable covalent inhibitors of human β-glucocerebrosidase.Chem. Commun. (Camb.)2024571139010.1039/C5CC03828F
     [Google Scholar]
  72. KerrI.D. LeeJ.H. FaradyC.J. MarionR. RickertM. SajidM. PandeyK.C. CaffreyC.R. LegacJ. HansellE. McKerrowJ.H. CraikC.S. RosenthalP.J. BrinenL.S. Vinyl sulfones as antiparasitic agents and a structural basis for drug design.J. Biol. Chem.200928438256972570310.1074/jbc.M109.014340 19620707
     [Google Scholar]
  73. SchneiderT.H. RiegerM. AnsorgK. SobolevA.N. SchirmeisterT. EngelsB. GrabowskyS. Vinyl sulfone building blocks in covalently reversible reactions with thiols.New J. Chem.20153975841585310.1039/C5NJ00368G
     [Google Scholar]
  74. LiuY. MaC. LiY. LiM. CuiT. ZhaoX. LiZ. JiaH. WangH. XiuX. HuD. ZhangR. WangN. LiuP. YangH. ChengM. Design, synthesis and biological evaluation of carbamate derivatives incorporating multifunctional carrier scaffolds as pseudo-irreversible cholinesterase inhibitors for the treatment of Alzheimer’s disease.Eur. J. Med. Chem.202426511607110.1016/j.ejmech.2023.116071 38157596
     [Google Scholar]
  75. ZhangH. WangY. WangY. LiX. WangS. WangZ. Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer’s disease.Eur. J. Med. Chem.202224011460610.1016/j.ejmech.2022.114606 35858523
     [Google Scholar]
  76. LiL. ChennaB.C. YangK.S. ColeT.R. GoodallZ.T. GiardiniM. MoghadamchargariZ. HernandezE.A. GomezJ. CalvetC.M. BernatchezJ.A. MellottD.M. ZhuJ. RademacherA. ThomasD. BlankenshipL.R. DrelichA. LaganowskyA. TsengC.T.K. LiuW.R. WandA.J. Cruz-ReyesJ. Siqueira-NetoJ.L. MeekT.D. Self-masked aldehyde inhibitors: A novel strategy for inhibiting cysteine proteases.J. Med. Chem.20216415112671128710.1021/acs.jmedchem.1c00628 34288674
     [Google Scholar]
  77. KonstantinidouM. VisserE.J. VandenboornE. ChenS. JaishankarP. OvermansM. DuttaS. NeitzR.J. RensloA.R. OttmannC. BrunsveldL. ArkinM.R. Structure-based optimization of covalent, small-molecule stabilizers of the 14-3-3σ/ERα protein-protein interaction from nonselective fragments.J. Am. Chem. Soc.202314537203282034310.1021/jacs.3c05161 37676236
     [Google Scholar]
  78. TroupR.I. FallanC. BaudM.G.J. Current strategies for the design of PROTAC linkers: A critical review.Explor. Target. Antitumor Ther.20201527331210.37349/etat.2020.00018 36046485
     [Google Scholar]
  79. BancetA. RaingevalC. LombergetT. Le BorgneM. GuichouJ.F. KrimmI. Fragment linking strategies for structure-based drug design.J. Med. Chem.20206320114201143510.1021/acs.jmedchem.0c00242 32539387
     [Google Scholar]
  80. PaivaS.L. CrewsC.M. Targeted protein degradation: nlms of PROTAC design.Curr. Opin. Chem. Biol.20195011111910.1016/j.cbpa.2019.02.022 31004963
     [Google Scholar]
  81. KaoC.T. LinC.T. ChouC.L. LinC.C. Fragment linker prediction using the deep encoder-decoder network for PROTACs drug design.J. Chem. Inf. Model.202363102918292710.1021/acs.jcim.2c01287 37150933
     [Google Scholar]
  82. BaghbeheshtiS. HadadianS. EidiA. PishkarL. RahimiH. Effect of flexible and rigid linkers on biological activity of recombinant tetramer variants of S3 antimicrobial peptide.Int. J. Pept. Res. Ther.202127145746210.1007/s10989‑020‑10095‑7
     [Google Scholar]
  83. KirschP. HartmanA.M. HirschA.K.H. EmptingM. Concepts and core principles of fragment-based drug design.Molecules20192423430910.3390/molecules24234309 31779114
     [Google Scholar]
  84. LuW. KosticM. ZhangT. CheJ. PatricelliM.P. JonesL.H. ChouchaniE.T. GrayN.S. Fragment-based covalent ligand discovery.RSC Chem. Biol.20212235436710.1039/D0CB00222D 34458789
     [Google Scholar]
  85. BoikeL. HenningN.J. NomuraD.K. Advances in covalent drug discovery.Nat. Rev. Drug Discov.2022211288189810.1038/s41573‑022‑00542‑z 36008483
     [Google Scholar]
  86. BarikD. ThurakkalL. JoseA. PorelM. Click chemistry: A tool for functionalization.Click Chemistry.CRC Press202412315010.1201/9781003403340‑7
     [Google Scholar]
  87. OyedeleA.Q.K. OgunlanaA.T. BoyenleI.D. AdeyemiA.O. RitaT.O. AdelusiT.I. Abdul-HammedM. ElegbeleyeO.E. OdunitanT.T. Docking covalent targets for drug discovery: Stimulating the computer-aided drug design community of possible pitfalls and erroneous practices.Mol. Divers.20232741879190310.1007/s11030‑022‑10523‑4 36057867
     [Google Scholar]
  88. SchaeferD. ChengX. Recent advances in covalent drug discovery.Pharmaceuticals202316566310.3390/ph16050663 37242447
     [Google Scholar]
  89. GhoshA.K. SamantaI. MondalA. LiuW.R. Covalent inhibition in drug discovery.ChemMedChem201914988990610.1002/cmdc.201900107 30816012
     [Google Scholar]
  90. MaX. SlomanD.L. DuggalR. AndersonK.D. BallardJ.E. BharathanI. BrynczkaC. GathiakaS. HendersonT.J. LyonsT.W. MillerR. MunsellE.V. OrthP. OtteR.D. PalaniA. RankicD.A. RobinsonM.R. SatherA.C. SolbanN. SongX.S. WenX. XuZ. YangY. YangR. DayP.J. StoeckA. BennettD.J. HanY. Discovery of MK-1084: An orally bioavailable and low-dose KRAS G12C inhibitor.J. Med. Chem.20246713110241105210.1021/acs.jmedchem.4c00572 38924388
     [Google Scholar]
  91. LanmanB.A. AllenJ.R. AllenJ.G. AmegadzieA.K. AshtonK.S. BookerS.K. ChenJ.J. ChenN. FrohnM.J. GoodmanG. KopeckyD.J. LiuL. LopezP. LowJ.D. MaV. MinattiA.E. NguyenT.T. NishimuraN. PickrellA.J. ReedA.B. ShinY. SiegmundA.C. TamayoN.A. TegleyC.M. WaltonM.C. WangH.L. WurzR.P. XueM. YangK.C. AchantaP. BartbergerM.D. CanonJ. HollisL.S. McCarterJ.D. MohrC. RexK. SaikiA.Y. San MiguelT. VolakL.P. WangK.H. WhittingtonD.A. ZechS.G. LipfordJ.R. CeeV.J. Discovery of a covalent inhibitor of KRAS G12C (AMG 510) for the treatment of solid tumors.J. Med. Chem.2020631526510.1021/acs.jmedchem.9b01180 31820981
     [Google Scholar]
/content/journals/coc/10.2174/0113852728361926250123092017
Loading
Covalent Inhibitors - An Overview of Design Process, Challenges and Future Directions
Current Organic Chemistry 29, 1424 (2025); https://doi.org/10.2174/0113852728361926250123092017
/content/journals/coc/10.2174/0113852728361926250123092017
/content/journals/coc/10.2174/0113852728361926250123092017
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): Covalent inhibitors; electrophiles; inhibitor design; linker; target residues; warhead

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test