Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies

Can the pharmaceutical industry reduce attrition rates?

Kola, I., & Landis, J. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1470 · Cited by 4,167

A systematic review of the associations between dose regimens and medication compliance

Claxton, A. J., Cramer, J., & Pierce, C. (2001) · Clinical Therapeutics · doi:10.1016/s0149-2918(01)80109-0 · Cited by 2,388

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118

The resurgence of covalent drugs

Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873

Identifying and Characterizing Binding Sites and Assessing Druggability

Halgren, T. A. (2009) · Journal of Chemical Information and Modeling · doi:10.1021/ci800324m · Cited by 1,808

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Honigberg, L. A., Smith, A. M., Sirisawad, M., Verner, E., Loury, D., Chang, B., Li, S., Pan, Z., Thamm, D. H., Miller, R. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004594107 · Cited by 1,561

ACETAMINOPHEN-INDUCED HEPATIC NECROSIS. II. ROLE OF COVALENT BINDING IN VIVO

Jollow, D. J., Mitchell, J. R., Potter, W. Z., Davis, D. C., Gillette, J. R., & Brodie, B. B. (1973) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)29664-1 · Cited by 1,203

Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway

Linker, R. A., Lee, D.-H., Ryan, S., van Dam, A. M., Conrad, R., Bista, P., Zeng, W., Hronowsky, X., Buko, A., Chollate, S., et al. (2011) · Brain · doi:10.1093/brain/awq386 · Cited by 1,155

Acetaminophen-Induced Hepatic Necrosis

Jollow, D. J., Thorgeirsson, S. S., Potter, W. Z., Hashimoto, M., & Mitchell, J. R. (2008) · Pharmacology · doi:10.1159/000136547 · Cited by 1,091

The quest to overcome resistance to EGFR-targeted therapies in cancer

Chong, C. R., & Janne, P. A. (2013) · Nature Medicine · doi:10.1038/nm.3388 · Cited by 1,076

Design, synthesis and antitumor activity of potent and safe para-quinone methides derivatives in vitro and in vivo

Li, P., Ma, Y., Wang, K., Shi, X., Yang, J., & Liu, G. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113893 · Cited by 11

What Have We Learned by Resurrecting the 1918 Influenza Virus?

Gilbertson, B. P., & Subbarao, K. (2023) · Annual Review of Virology · doi:10.1146/annurev-virology-111821-104408 · Cited by 13

Impact of the structures of macrocyclic Michael acceptors on covalent proteasome inhibition

Kitahata, S., Yakushiji, F., & Ichikawa, S. (2017) · Chemical Science · doi:10.1039/c7sc02941a · Cited by 11

Highly tunable thiosulfonates as a novel class of cysteine protease inhibitors with anti-parasitic activity against Schistosoma mansoni

Ward, D. J., van de Langemheen, H., Koehne, E., Kreidenweiss, A., & Liskamp, R. M. J. (2019) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2019.05.014 · Cited by 11

Cyanide-Free Synthesis of Air Stable N-Substituted Li and K Cyanamide Salts from Tetrazoles. Applications toward the Synthesis of Primary and Secondary Cyanamides as Precursors to Amidines

Duchamp, E., & Hanessian, S. (2020) · Organic Letters · doi:10.1021/acs.orglett.0c03085 · Cited by 11

An Innovative Approach to Address Neurodegenerative Diseases through Kinase-Targeted Therapies: Potential for Designing Covalent Inhibitors

Bhujbal, S. P., & Hah, J. (2023) · Pharmaceuticals · doi:10.3390/ph16091295 · Cited by 10

Discovery of a Tunable Heterocyclic Electrophile 4-Chloro-pyrazolopyridine That Defines a Unique Subset of Ligandable Cysteines

Kim, H., Byun, D. P., Thakur, K., Ritchie, J., Xie, Y., Holewinski, R. J., Suazo, K. F., Stevens, M., Liechty, H., Tagirasa, R., et al. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00025 · Cited by 10

DNA encoded peptide library for SARS-CoV-2 3CL protease covalent inhibitor discovery and profiling

Xing, Y., Zhang, H., Wang, Y., Zong, Z., Bogyo, M. S., & Chen, S. (2024) · RSC Chemical Biology · doi:10.1039/d4cb00097h · Cited by 10

Furan warheads for covalent trapping of weak protein–protein interactions: cross-linking of thymosin β4 to actin

Miret‐Casals, L., Vannecke, W., Hoogewijs, K., Arauz‐Garofalo, G., Gay, M., Díaz‐Lobo, M., Vilaseca, M., Ampè, C., Troys, M. V., & Madder, A. (2021) · Chemical Communications · doi:10.1039/d1cc01731d · Cited by 10

Targeted Covalent Inhibition of Small CTD Phosphatase 1 to Promote the Degradation of the REST Transcription Factor in Human Cells

Medellin, B. P., Yang, W., Konduri, S., Dong, J., Irani, S., Wu, H., Matthews, W. L., Zhang, Z., Siegel, D., & Zhang, Y. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01655 · Cited by 10

Exploration of SARS-CoV-2 Mpro Noncovalent Natural Inhibitors Using Structure-Based Approaches

Duong, C. Q., & Nguyen, P. T. V. (2023) · ACS Omega · doi:10.1021/acsomega.2c07259 · Cited by 10

αβ,α′β′-Diepoxyketones are mechanism-based inhibitors of nucleophilic cysteine enzymes

de Munnik, M., Lithgow, J., Brewitz, L., Christensen, K. E., Bates, R. H., Rodríguez-Miquel, B., & Schofield, C. J. (2023) · Chemical Communications · doi:10.1039/d3cc02932h · Cited by 9

Electrophile Determines Cellular Phenotypes among XPO1-Targeting Small Molecules

Chen, Y., Shen, Y., Yan, D. F., Ghazala, M., de Gialluly, M. A. S., Srinivasan, R., Farrar, A. N., Friedrich, R. M., & Adams, D. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00754 · Cited by 10

Design, synthesis, and cytotoxic evaluation of novel scopoletin derivatives

Shi, W., Zhang, J., Bao, N., Guan, F., Chen, L., & Sun, J. (2017) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13120 · Cited by 10

A High-Content Screen Reveals New Small-Molecule Enhancers of Ras/Mapk Signaling as Probes for Zebrafish Heart Development

Saydmohammed, M., Vollmer, L. L., Onuoha, E. O., Maskrey, T. S., Gibson, G. A., Watkins, S. C., Wipf, P., Vogt, A., & Tsang, M. (2018) · Molecules · doi:10.3390/molecules23071691 · Cited by 10

Direct screening of a target-specific covalent binder: stringent regulation of warhead reactivity in a matchmaking environment

Tabuchi, Y., Watanabe, T., Katsuki, R., Ito, Y., & Taki, M. (2021) · Chemical Communications · doi:10.1039/d1cc01773j · Cited by 10

On the Origin of the Different Reversible Characters of Salinosporamide A and Homosalinosporamide A in the Covalent Inhibition of the Human 20S Proteasome

Serrano-Aparicio, N., Moliner, V., & Świderek, K. (2021) · ACS Catalysis · doi:10.1021/acscatal.1c02614 · Cited by 10

4‐Iodopyrimidine Labeling Reveals Nuclear Translocation and Nuclease Activity for Both MIF and MIF2**

Xiao, Z., Chen, D., Mulder, F., Song, S., van der Wouden, P. E., Cool, R. H., Melgert, B. N., Poelarends, G. J., & Dekker, F. J. (2021) · Chemistry - A European Journal · doi:10.1002/chem.202103030 · Cited by 10

Reversible Covalent Reaction of Levosimendan with Cardiac Troponin C in Vitro and in Situ

Klein, B. A., Reiz, B., Robertson, I. M., Irving, M., Li, L., Sun, Y., & Sykes, B. D. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00109 · Cited by 10

Evaluation of Bruton’s Tyrosine Kinase (BTK) inhibition with alternative doses of ibrutinib in subjects with Chronic Lymphocytic Leukemia (CLL)

Ouerdani, A., Valenzuela, B., Treijtel, N., Haddish‐Berhane, N., Desphande, S., Srinivasan, S. S., Smith, E., & Ruixo, J. J. P. (2025) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-025-04753-0 · Cited by 9

Subnanomolar Cathepsin S Inhibitors with High Selectivity: Optimizing Covalent Reversible α‐Fluorovinylsulfones and α‐Sulfonates as Potential Immunomodulators in Cancer

Fuchs, N. S., Meta, M., Lantzberg, B., Bros, M., Kuan, S. L., Weil, T., & Schirmeister, T. (2023) · ChemMedChem · doi:10.1002/cmdc.202300160 · Cited by 8

Natural product-inspired molecules for covalent inhibition of SHP2 tyrosine phosphatase

Liang, W., Krabill, A. D., Gallagher, K. S., Muli, C. S., Qu, Z., Trader, D. J., Zhang, Z., & Dai, M. (2024) · Tetrahedron · doi:10.1016/j.tet.2024.133918 · Cited by 9

β-Lactones: A Novel Class of Ca2+-Independent Phospholipase A2 (Group VIA iPLA2) Inhibitors with the Ability To Inhibit β-Cell Apoptosis

Dedaki, C., Kokotou, M. G., Mouchlis, V. D., Limnios, D., Lei, X., Mu, C. T., Ramanadham, S., Magrioti, V., Dennis, E. A., & Kokotos, G. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01216 · Cited by 9

Synthesis and structure-activity relationships of small-molecular di-basic esters, amides and carbamates as flaviviral protease inhibitors

Sundermann, T. R., Benzin, C. V., Dražić, T., & Klein, C. D. P. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.025 · Cited by 9

Non-stoichiometric inhibition in integrated lead finding – a literature review

Klumpp, M. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2016.1128892 · Cited by 10

Molecular Insights into the Impact of Mutations on the Binding Affinity of Targeted Covalent Inhibitors of BTK

Awoonor‐Williams, E., & Abu‐Saleh, A. A. A. (2024) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.4c00310 · Cited by 8

Ligandability at the Membrane Interface of GPx4 Revealed through a Reverse Micelle Fragment Screening Platform

Labrecque, C. L., & Fuglestad, B. (2024) · JACS Au · doi:10.1021/jacsau.4c00427 · Cited by 8

Research progress on covalent inhibitors targeting alkaline amino acids

Zhao, B., Xu, S., Zhou, S., Jiang, X., Jiang, A., Lei, H., & Zhai, X. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108800 · Cited by 8

A diastereoselective three-component reaction for the assembly of succinimide and isatin hybrid molecules with potent anticancer activities

Yuan, H., Guo, Y., Zhang, Z., Sha, H., He, Y., Xu, X., & Hu, W. (2022) · Molecular Diversity · doi:10.1007/s11030-022-10457-x · Cited by 8

Design, synthesis and biological activity evaluation of novel covalent S-acylation inhibitors

Yu, W., Yang, K., Zhao, M., Liu, H., You, Z., Liu, Z., Qiao, X., & Song, Y. (2023) · Molecular Diversity · doi:10.1007/s11030-023-10633-7 · Cited by 8

Development and Application of Small Molecule–Peptide Conjugates as Cathepsin K-Specific Covalent Irreversible Inhibitors in Human Osteoclast and Lung Cancer

Dey, G., Yakobovich, E., Loboda, J., Sinai‐Turyansky, R., Abramovitch‐Dahan, C., Merquiol, E., Sridharan, N., Itzhak, G., Turk, B., Wald, O., et al. (2025) · JACS Au · doi:10.1021/jacsau.4c00840 · Cited by 8

Small-molecules that covalently react with a human prolyl hydroxylase – towards activity modulation and substrate capture

Bush, J. T., Leśniak, R. K., Yeh, T.-L., Belle, R., Kramer, H., Tumber, A., Chowdhury, R., Flashman, E., Mecinović, J., & Schofield, C. J. (2018) · Chemical Communications · doi:10.1039/c8cc07706a · Cited by 8

Estimating the binding energetics of reversible covalent inhibitors of the SARS-CoV-2 main protease: an in silico study

Awoonor‐Williams, E. (2022) · Physical Chemistry Chemical Physics · doi:10.1039/d2cp03080b · Cited by 9

Analysis of the ERK Pathway Cysteinome for Targeted Covalent Inhibition of RAF and MEK Kinases

Romany, A., Liu, R., Zhan, S., Clayton, J., & Shen, J. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00014 · Cited by 8

Hydroxylammonium derivatives for selective active-site lysine modification in the anti-virulence bacterial target DHQ1 enzyme

Maneiro, M., Lence, E., Sanz‐Gaitero, M., Otero, J. M., van Raaij, M. J., Thompson, P., Hawkins, A. R., & González‐Bello, C. (2019) · Organic Chemistry Frontiers · doi:10.1039/c9qo00453j · Cited by 8

How does cross-conjugation influence thiol additions to enones? A computational study of thiol trapping by the naturally occurring divinyl ketones zerumbone and α-santonin

Ting, J. Y. C., Roseli, R. B., & Krenske, E. H. (2020) · Organic & Biomolecular Chemistry · doi:10.1039/c9ob02709b · Cited by 8

HER2 transmembrane domain mutation: comprehensive characteristics and real-world evidence of treatment response in Chinese lung adenocarcinoma

Jia, Z., Xing, J., Li, J., Wang, W., Wang, Y., Song, Y., Yang, X., Xue, J., Ye, J., Li, B., et al. (2021) · Translational Lung Cancer Research · doi:10.21037/tlcr-21-107 · Cited by 7

Sulfopin, a selective covalent inhibitor of Pin1, blocks Myc-driven tumor initiation and growth in vivoPreprint

Dubiella, C., Pinch, B. J., Zaidman, D., Manz, T. D., Poon, E., He, S., Resnick, E., Langer, E. M., Daniel, C. J., Seo, H., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.20.998443 · Cited by 8

Discovery of Novel N-Acylpyrazoles as Potent and Selective Thrombin InhibitorsPreprint

Short, K. M., Estiarte, M. A., Pham, S. M., Williams, D. C., Igoudin, L., Dash, S., Sandoval, N., Datta, A., Pozzi, N., Di, E., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4202449 · Cited by 8

Strategy for cysteine-targeting covalent inhibitors screening using in-house database based LC-MS/MS and drug repurposing

Hu, X., Wu, J., He, Q., Xiong, Z., & Li, N. (2024) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2024.101045 · Cited by 8

Dynamics Playing a Key Role in the Covalent Binding of Inhibitors to Focal Adhesion Kinase

Liu, Y., Tan, J., Hu, S., Hussain, M., Qiao, C., Tu, Y., Lu, X., & Zhou, Y. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c00418 · Cited by 7

Tuning isatoic anhydrides’ lysine ligation chemistry for bioconjugation and drug delivery

Tiwari, S., Senthil, S., Khanna, S., Duraisamy, S., Vechalapu, S. K., Mallojjala, S. C., & Allimuthu, D. (2024) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2024.102260 · Cited by 7

Small-molecule FGFR-targeted medicinal chemistry: Advances since 2020 and future perspectives

Yue, H., Wang, Y., Zhang, N., Xing, J., Wang, T., Bao, Y., Hou, Y., & Zhao, Y. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118117 · Cited by 9

Peptide-Based Targeted Covalent Inhibitors

Cao, F., Guo, R.-C., Zhang, Z., & Yu, Z. (2025) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.5c18100 · Cited by 8

A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl-1

Alboreggia, G., Muzzarelli, K. M., Assar, Z., & Pellecchia, M. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02199 · Cited by 7

Cyanoacrylamides as versatile scaffolds in medicinal chemistry: From synthetic strategies to therapeutic applications

Abdelhamid, I. A., Barakat, K., Mohamed, F. G., Ragheb, M. A., Diab, H. M., Abdelmoniem, A. M., & Elwahy, A. H. M. (2026) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2026.145256 · Cited by 7

Cell Signaling by Tryptophan Catabolism

Torrelli-Diljohn, A., Kulkarni, B., & Vitturi, D. A. (2026) · Biochemistry · doi:10.1021/acs.biochem.6c00179 · Cited by 7

Target Engagement Measures in Preclinical Drug Discovery: Theory, Methods, and Case Studies

Durham, T. B., & Wiley, M. R. (2017) · AAPS advances in the pharmaceutical sciences series · doi:10.1007/978-3-319-50042-3_3 · Cited by 7

Self‐Immolation of a Bacterial Dehydratase Enzyme by its Epoxide Product

Lence, E., Maneiro, M., Sanz‐Gaitero, M., van Raaij, M. J., Thompson, P., Hawkins, A. R., & González‐Bello, C. (2020) · Chemistry - A European Journal · doi:10.1002/chem.202000759 · Cited by 7

Serendipitous Identification of a Covalent Activator of Liver Pyruvate Kinase

Battisti, U. M., Gao, C., Nilsson, O., Akladios, F. N., Lulla, A., Bogucka, A., Nain‐Perez, A., Håversen, L., Kim, W., Borén, J., et al. (2022) · ChemBioChem · doi:10.1002/cbic.202200339 · Cited by 7

bioTCIs: Middle-to-Macro Biomolecular Targeted Covalent Inhibitors Possessing Both Semi-Permanent Drug Action and Stringent Target Specificity as Potential Antibody Replacements

Yang, J., Tabuchi, Y., Katsuki, R., & Taki, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043525 · Cited by 8

Electrophilic Nitro-Fatty Acids: Nitric Oxide and Nitrite-Derived Metabolic and Inflammatory Signaling Mediators

Freeman, B. Α., Pekarová, M., Rubbo, H., & Trostchansky, A. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804273-1.00016-8 · Cited by 7

Elucidation of chemical modifier reactivity towards peptides and proteins and the analysis of specific fragmentation by matrix-assisted laser desorption/ionization collision-induced dissociation tandem mass spectrometry.

Rühl, M., Kühn, B., Roos, J., Maier, T., Steinhilber, D., & Karas, M. (2018) · Rapid Communications in Mass Spectrometry · doi:10.1002/rcm.8223 · Cited by 6

Function‐Oriented and Modular (+/−)‐cis‐Pseudoguaianolide Synthesis: Discovery of New Nrf2 Activators and NF‐κB Inhibitors

Emmetiere, F., Ratnayake, R., Schares, H. A. M., Jones, K. F. M., Bevan–Smith, E., Luesch, H., Harki, D. A., & Grenning, A. J. (2021) · Chemistry - A European Journal · doi:10.1002/chem.202100038 · Cited by 8

Biotransformation and bioactivation reactions – 2018 literature highlights

Khojasteh, S. C., Bumpus, N. N., Driscoll, J. P., Miller, G. P., Mitra, K., Rietjens, I. M. C. M., & Zhang, D. (2019) · Drug Metabolism Reviews · doi:10.1080/03602532.2019.1615937 · Cited by 7

Crystal structure of human 17beta-HSD type 1 in ternary complex with PBRM and NADP+

Li, T., & Lin, S. X. (2018) · Worldwide Protein Data Bank · doi:10.2210/pdb6cge/pdb · Cited by 7

Mechanistic Characterization of Covalent Enzyme Inhibition by Isothermal Titration Calorimetry Kinetic Competition (ITC-KC)

Hennecker, C. D., Venegas, F., Wang, G., Stille, J. K., Miłaczewska, A., Moitessier, N., & Mittermaier, A. (2025) · Analytical Chemistry · doi:10.1021/acs.analchem.4c04003 · Cited by 6

Kinetic Modeling of Covalent Inhibition: Effects of Rapidly Fluctuating Intermediate States

Ghaby, K., & Roux, B. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c00952 · Cited by 5

N’-Aryl α,β-Unsaturated Fatty Acid Hydrazides with Broad Antifungal Activity: Design, Bioactivity, and Action Mechanism

Du, T., Bai, R., Wang, Y., Zhao, Z., Zhou, C., Zhang, Y., Xie, B., She, D., Zhou, B., & Zhou, L. (2025) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.5c04751 · Cited by 6

A perspective on cysteine-reactive activity-based probes

Nuber, C. M., Schwab, M. A., & Konrad, D. B. (2025) · Organic & Biomolecular Chemistry · doi:10.1039/d5ob00905g · Cited by 6

A practical method for determining the rate of covalent modification of fragments and leads

Jeon, J., Kholodar, S. A., Tran, B. H., Mallinger, K. E., Erlanson, D. A., & Everley, R. A. (2025) · Nature Communications · doi:10.1038/s41467-025-66924-0 · Cited by 8

Covalent Antiviral Agents

Mirzaie, S., Abdi, F., GhavamiNejad, A., Lu, B., & Wu, X. Y. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-16-0267-2_11 · Cited by 6

Synthesis of Nitrogen‐Containing Goniothalamin Analogues with Higher Cytotoxic Activity and Selectivity against Cancer Cells

Meirelles, M. A., Braga, C. B., Ornelas, C., & Pilli, R. A. (2019) · ChemMedChem · doi:10.1002/cmdc.201900281 · Cited by 6

A CDR-based approach to generate covalent inhibitory antibody for human rhinovirus protease

Cheng, Y., Wu, J., Han, Y., Xu, J., Da, Y., Zhao, Q., Guo, G., Zhou, Y., Chen, Y., Liu, J., et al. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116219 · Cited by 6

Parthenolide reveals an allosteric mode to inhibit the deISGylation activity of SARS-CoV‑2 papain-like protease

Zou, Z., Shan, H., Sun, D., Li, X., Shi, Y., Wan, J., Zhou, A., Wu, Y., Xu, H., Lei, H., et al. (2022) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2022092 · Cited by 6

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure

Dempe, D. P., Ji, C., Liu, P., & Brummond, K. M. (2022) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.2c01530 · Cited by 6

Understanding Cysteine Chemistry Using Conventional and Serial X-ray Protein Crystallography

Smith, N., & Wilson, M. A. (2022) · Crystals · doi:10.3390/cryst12111671 · Cited by 6

Serine Hydrolase Activity‐Based Probes for Use in Chemical Proteomics

Racioppo, B., Qiu, N., & Adibekian, A. (2023) · Israel Journal of Chemistry · doi:10.1002/ijch.202300016 · Cited by 6

Design, Synthesis and Anti-Proliferative Activities of 2,6-Substituted Thieno[3,2-d]pyrimidine Derivatives Containing Electrophilic Warheads

Zhang, Q., Hu, Z.-L., Shen, Q., Chen, Y., & Lu, W. P. (2017) · Molecules · doi:10.3390/molecules22050788 · Cited by 6

Strategic Design of Catalytic Lysine‐Targeting Reversible Covalent BCR‐ABL Inhibitors**

Quach, D., Tang, G., Anantharajan, J., Baburajendran, N., Poulsen, A., Wee, J. L. K., Retna, P., Li, R., Liu, B., Tee, D. H. Y., et al. (2021) · Angewandte Chemie · doi:10.1002/ange.202105383 · Cited by 7

The Discovery of Novel Small Oxindole‐Based Inhibitors Targeting the SARS‐CoV‐2 Main Protease (Mpro)

Alzyoud, L., Mahgoub, R. E., Mohamed, F. E., Ali, B. R., Ferreira, J. C., Rabeh, W. M., Atatreh, N., & Ghattas, M. A. (2023) · Chemistry & Biodiversity · doi:10.1002/cbdv.202301176 · Cited by 6

Elucidating the Catalytic Power of Glutamate Racemase by Investigating a Series of Covalent Inhibitors

Vance, N. R., Witkin, K. R., Rooney, P. W., Li, Y., Pope, M. R., & Spies, M. A. (2018) · ChemMedChem · doi:10.1002/cmdc.201800592 · Cited by 6

Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond

Serafim, R. A. M., Gehringer, M., & Borsari, C. (2024) · Pharmaceuticals · doi:10.3390/ph17020206 · Cited by 8

A high-throughput selection system for fast-acting covalent protein drugs

Fan, Q., Mei, J., Li, T., Zang, C., Li, M., Tang, J., Xu, Y. C., Yu, G., Liu, D., Chen, K., et al. (2026) · Science · doi:10.1126/science.adv3081 · Cited by 5

The amino-dipeptidyl peptidases DPP8 and DPP9: Purification and enzymatic assays

Donzelli, L., Bolgi, O., & Geiss‐Friedlander, R. (2023) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/bs.mie.2023.02.013 · Cited by 5

Diastereoselective ZnCl2-Mediated Joullié–Ugi Three-Component Reaction for the Preparation of Phosphorylated N-Acylaziridines from 2H-Azirines

Allende, J., Olaizola, I., de Retana, A. M. O., Palácios, F., & Santos, J. M. D. L. (2024) · Molecules · doi:10.3390/molecules29051023 · Cited by 5

Design, preparation and biological evaluation of new Rociletinib-inspired analogs as irreversible EGFR inhibitors to treat non-small-cell-lung cancer

Konsue, A., Lamtha, T., Gleeson, D., Jones, D. J. L., Britton, R. G., Pickering, J., Choowongkomon, K., & Gleeson, M. P. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117906 · Cited by 5

Targeted anticancer pre-vinylsulfone covalent inhibitors of carbonic anhydrase IX

Vaškevičius, A., Baronas, D., Leitāns, J., Kvietkauskaitė, A., Rukšėnaitė, A., Manakova, E., Toleikis, Z., Kaupinis, A., Kazāks, A., Gedgaudas, M., et al. (2024) · eLife · doi:10.7554/elife.101401.3 · Cited by 9

Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development

Hossain, M. A., Brahme, R. R., Miller, B. C., Amin, J., de Barros, M., Schneider, J. L., Auclair, J. R., Mattos, C., Wang, Q., Agar, N. Y. R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56985-6 · Cited by 6

A comprehensive review of small molecule drugs approved by the FDA in 2025: advance and prospect

Bai, Y., Li, R., Zhang, X., Seng, D., Xu, Y., Zhang, S., & Yuan, S. (2026) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2026.2704735 · Cited by 5

Molecular modeling-guided optimization of acetylcholinesterase reactivators: A proof for reactivation of covalently inhibited targets

Wei, Z., Yang, J. W., Liu, Y., Nie, H., Yao, L., Yang, J., Guo, L., Zheng, Z., & Ouyang, Q. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113286 · Cited by 5

The Design, Structure–Activity, and Kinetic Studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl Sulfamates as Steroid Sulfatase Inhibitors

Chang, C.-N., Lin, I.-C., Lin, T.-S., Chiu, P.-F., Lu, Y., Narwane, M., Liu, I., Hng, Y., Tsai, K., Lin, M., et al. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.106148 · Cited by 5

Synthesis and bioactivity studies of covalent inhibitors derived from (-)-Chaetominine

Zhou, X., Feng, X., Wang, D., Chen, D., Wu, G., Yan, Z., Lyu, X., Wang, H., Yang, J.-M., & Zhao, Y. (2021) · Journal of Molecular Structure · doi:10.1016/j.molstruc.2021.130694 · Cited by 5

Comparison of irreversible inhibition targeting HSP72 protein: the resurgence of covalent drug developments

Aljoundi, A., El-Rashedy, A. A. E., & Soliman, M. E. S. (2021) · Molecular Simulation · doi:10.1080/08927022.2021.1949457 · Cited by 5

Dual roles of drug or its metabolite−protein conjugate: Cutting‐edge strategy of drug discovery using shotgun proteomics

Gong, S., Hu, X., Chen, S., Sun, B., Wu, J., & Li, N. (2022) · Medicinal Research Reviews · doi:10.1002/med.21889 · Cited by 5

ARCaDia: single-round screening of a DNA-type targeted covalent binder possessing a latent warhead

Taki, M., Kuwahara, M., Li, C., Tomoda, N., Miyashita, N., Kan, T., & Yang, J. (2024) · Chemical Communications · doi:10.1039/d4cc04594g · Cited by 4

Design, Synthesis, and Molecular Evaluation of S N Ar‐Reactive N ‐(6‐Fluoro‐3‐Nitropyridin‐2‐yl)Isoquinolin‐3‐Amines as Covalent USP7 Inhibitors Reveals an Unconventional Binding Mode

Ernst, L. N., Stahlecker, J., Mier, F., Serafim, R. A. M., Wydra, V. R., Masberg, B., Jaag, S., Knappe, C., Lämmerhofer, M., Stehle, T., et al. (2025) · Archiv der Pharmazie · doi:10.1002/ardp.70053 · Cited by 4

Covalent chemistry in targeted protein degradation

Tan, J., Liang, Y., Shao, S., & Shen, Y. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115777 · Cited by 4

A comprehensive review of small molecule drugs approved by the FDA in 2024: Advance and prospect

Bai, Y., Duan, Q.-C., Seng, D., Xu, Y., Ren, H., Zhang, J., Shen, D., Yang, L., Liu, H., & Yuan, S. (2025) · Chinese Chemical Letters · doi:10.1016/j.cclet.2025.111025 · Cited by 4

Penicillin acylase and O-aryloxycarbonyl hydroxamates: Two acyl-enzymes, one leading to hydrolysis, the other to inactivation

Adediran, S. A., & Pratt, R. F. (2016) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2016.12.009 · Cited by 4

A computational study of the influence of methyl substituents on competitive ring closure to α- and β-lactones

Wilson, P., & Williams, I. H. (2017) · Organic & Biomolecular Chemistry · doi:10.1039/c7ob01653k · Cited by 4

Distinguishing the optimal binding mechanism through reversible and irreversible inhibition analysis of HSP72 protein in cancer therapy

Aljoundi, A., El-Rashedy, A. A. E., & Soliman, M. E. S. (2021) · Computers in Biology and Medicine · doi:10.1016/j.compbiomed.2021.104301 · Cited by 4

Discovery of Covalent Drugs Targeting the Key Enzymes of SARS-CoV-2 Using SCARdock

Song, Q., Wang, Z., & Liu, S. (2021) · Methods in pharmacology and toxicology · doi:10.1007/7653_2020_56 · Cited by 2

Design and testing of selective inactivators against an antifungal enzyme target

Friday, S. N., Cheng, D. W., Zagler, S. G., Zanella, B. S., Dietz, J. D., Calbat, C. N., Roach, L. T., Bagnal, C., Faile, I. S., Halkides, C. J., et al. (2021) · Drug Development Research · doi:10.1002/ddr.21875 · Cited by 4

Selection Method of DNA-Encoded Chemical Library for Irreversible Covalent Binders

Zhu, Z. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2545-3_20 · Cited by 4

Mutate and Conjugate: A Method to Enable Rapid In-Cell Target Validation

Thomas, A., Serafini, M. T., Grant, E. K., Coombs, E. A. J., Bluck, J. P., Schiedel, M., McDonough, M. A., Reynolds, J. K., Lee, B., Platt, M. A., et al. (2023) · ACS Chemical Biology · doi:10.1021/acschembio.3c00437 · Cited by 3

Sequence‐Selective Covalent CaaX‐Box Receptors Prevent Farnesylation of Oncogenic Ras Proteins and Impact MAPK/PI3 K Signaling

Franz, M., Mörchen, B., Degenhart, C., Gülden, D., Shkura, O., Wolters, D. A., Koch, U., Klebl, B., Stoll, R., Helfrich, I., et al. (2021) · ChemMedChem · doi:10.1002/cmdc.202100167 · Cited by 4

BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides

Hermann, M. R., Tautermann, C. S., Sieger, P., Grundl, M. A., & Weber, A. (2023) · Pharmaceuticals · doi:10.3390/ph16010116 · Cited by 4

Covalent fragment inhibits intramembrane proteolysis

Eden, A., Zhao, J., Xiao, Y., Gibson, J., & Wang, C. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.958399 · Cited by 3

Warhead-bearing natural compounds for multi-pathway irreversible inhibition to overcome drug resistance in colorectal cancer

Hou, H.-P., Liu, X., Liu, W., Zhang, P., & Zhou, B. (2025) · Medical Oncology · doi:10.1007/s12032-025-02699-0 · Cited by 3

Drug development of covalent inhibitors

Dahal, U. P., & Wahlstrom, J. L. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-817134-9.00009-x · Cited by 2

Covalent inhibitors: a rational approach to drug discovery

Sutanto, F., Konstantinidou, M., & Dömling, A. (2020) · RSC Medicinal Chemistry · doi:10.1039/d0md00154f · Cited by 389

The resurgence of covalent drugs

Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873

Covalent drug – An emerging framework for targeted drug development

Bhole, R. P., Joshi, G. O., Kapare, H. S., Chikhale, R. V., & Chaudhari, S. Y. (2024) · Results in Chemistry · doi:10.1016/j.rechem.2024.101615 · Cited by 10

Perspective: The Re-emergence of Covalent Modulation in Drug DiscoveryPreprint

Jahic, M. (2025) · doi:10.22541/au.175637196.69046933/v1