# Hand review of covalent-drug candidates among ChEMBL 37 approved small molecules. See covalent-drugs-review-notes.md. # decision: covalent or not_covalent. definition: strict, broad or none. evidence: A = adduct shown by structure, mass spectrometry or label; B = accepted mechanism, adduct not directly characterized. chembl_id name decision definition warhead_class bond reversibility target_class target evidence basis CHEMBL3707348 Acalabrutinib covalent strict Butynamide Protein cysteine Irreversible Protein kinases BTK A 2-Butynamide adds to BTK Cys481; shown by crystal structure CHEMBL600 Acetylcysteine not_covalent none Thiol antioxidant; no covalent target CHEMBL4594350 Adagrasib covalent strict Acrylamide Protein cysteine Irreversible Small GTPases and other proteins KRAS G12C A Acrylamide adds to mutant Cys12 of KRAS; shown by crystal structure CHEMBL1173655 Afatinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR, HER2 A Acrylamide adds to EGFR Cys797; shown by crystal structure or mass spectrometry CHEMBL1467 Allopurinol not_covalent none Oxypurinol coordinates the reduced molybdenum centre; no covalent bond to the protein CHEMBL376359 Alogliptin not_covalent none Benzonitrile; non-covalent DPP-4 inhibitor CHEMBL1455 Altretamine not_covalent none Activation is described, but the DNA adduct chemistry is not established CHEMBL530 Amdinocillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1650818 Amdinocillin pivoxil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1082 Amoxicillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL174 Ampicillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1929396 Anagliptin covalent strict Nitrile Protein serine Reversible Proteases DPP-4 B Cyanopyrrolidine, the same warhead as vildagliptin; Ser630 imidate inferred from the class CHEMBL25 Aspirin covalent broad Aryl ester (acyl donor) Protein serine Irreversible Other enzymes Cyclooxygenase (COX-1 Ser529, COX-2 Ser516) A Acetylates the cyclooxygenase serine; shown by crystal structure and mass spectrometry CHEMBL1689063 Avibactam covalent strict Diazabicyclooctane Protein serine Reversible Bacterial cell-wall enzymes Beta-lactamases A Cyclic urea carbamoylates the active-site serine; ring closure is reversible; shown by crystal structure CHEMBL1489 Azacitidine covalent broad Azacytosine nucleoside Protein cysteine Irreversible Other enzymes DNA methyltransferase 1 (DNMT1) A Incorporated into DNA, where the 5-aza ring traps the methyltransferase cysteine; shown by crystal structure CHEMBL1537 Azlocillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL158 Aztreonam covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1583 Bacampicillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL408513 Belinostat not_covalent none Acrylamide-like hydroxamic acid that chelates zinc CHEMBL487253 Bendamustine covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; aziridinium ion crosslinks guanines CHEMBL162036 Benorilate not_covalent none Ester of aspirin and paracetamol; covalent action of the intact drug is not documented CHEMBL95889 Betaine not_covalent none Substrate CHEMBL218394 Boceprevir covalent strict Ketoamide Protein serine Reversible Proteases HCV NS3/4A protease A Alpha-ketoamide forms a hemiketal with the catalytic serine; shown by crystal structure CHEMBL325041 Bortezomib covalent strict Boronic acid Protein threonine Reversible Proteases 26S proteasome (beta-5 subunit) A Boronic acid forms a tetrahedral adduct with the N-terminal Thr1 hydroxyl; shown by crystal structure CHEMBL820 Busulfan covalent broad Alkyl sulfonate DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; alkylates guanine and crosslinks DNA CHEMBL334966 Cangrelor not_covalent none Reversible P2Y12 antagonist CHEMBL1773 Capecitabine covalent broad Fluoropyrimidine Protein cysteine Irreversible Other enzymes Thymidylate synthase (Cys195) A Metabolite FdUMP forms a covalent ternary complex with thymidylate synthase and folate; shown by crystal structure; prodrug of 5-FU CHEMBL1214 Carbenicillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1596 Carbenicillin indanyl covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL451887 Carfilzomib covalent strict Epoxyketone Protein threonine Irreversible Proteases 26S proteasome (beta-5 subunit) A Epoxyketone forms a morpholino ring with the Thr1 hydroxyl and amine; shown by crystal structure CHEMBL513 Carmustine covalent broad Nitrosourea DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; chloroethylation of guanine O6 and interstrand crosslinks CHEMBL680 Cefaclor anhydrous covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1644 Cefadroxil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1146 Cefamandole covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201218 Cefamandole nafate free base covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1435 Cefazolin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL927 Cefdinir covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL454446 Cefditoren pivoxil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL186 Cefepime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL3989974 Cefiderocol covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1541 Cefixime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201224 Cefmenoxime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201195 Cefmetazole covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1601 Cefonicid covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL507674 Cefoperazone covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201046 Ceforanide covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1730 Cefotaxime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL474579 Cefotetan covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1296 Cefotiam covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL996 Cefoxitin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201204 Cefpiramide covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL65794 Cefpirome covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1672 Cefpodoxime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201016 Cefpodoxime proxetil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL276568 Cefprozil anhydrous, (e)- covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL501122 Ceftaroline fosamil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL44354 Ceftazidime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1605 Ceftibuten covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL528 Ceftizoxime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1652606 Ceftobiprole medocaril free acid covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL2103872 Ceftolozane covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL161 Ceftriaxone covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1436 Cefuroxime covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1095930 Cefuroxime axetil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1727 Cephalexin anhydrous covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1200971 Cephaloglycin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL316157 Cephaloridine covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL617 Cephalothin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1599 Cephapirin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1604 Cephradine covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL515 Chlorambucil covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; aziridinium ion crosslinks guanines CHEMBL2107519 Chlornaphazine covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) B DNA alkylating agent; withdrawn for carcinogenicity CHEMBL1874750 Cinepazide not_covalent none Cinnamoyl amide, no covalent action CHEMBL777 Clavulanic acid covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Beta-lactamases A Natural product that acylates the catalytic serine; found by screening, so broad only CHEMBL1771 Clopidogrel covalent broad Thienopyridine (prodrug) Protein cysteine Irreversible GPCRs P2Y12 receptor A Liver metabolite thiol forms a disulfide with extracellular P2Y12 cysteines CHEMBL891 Cloxacillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL2095208 Cobicistat not_covalent none Mechanism-based CYP3A4 inactivation is a pharmacokinetic booster action, not an indication target CHEMBL291657 Crinecerfont not_covalent none Alkyne is not a warhead CHEMBL484785 Crisaborole not_covalent none Benzoxaborole that coordinates PDE4 metal ions; no covalent bond to the protein CHEMBL1200356 Cyclacillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL88 Cyclophosphamide anhydrous covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; liver activation releases the mustard CHEMBL771 Cycloserine not_covalent none Forms an adduct with the PLP cofactor, a freely dissociating coenzyme CHEMBL476 Dacarbazine covalent broad Methylating triazene or hydrazine DNA Irreversible DNA DNA (guanine) B DNA alkylating agent; methylates guanine O6 and N7 after activation CHEMBL2110732 Dacomitinib anhydrous covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR, HER2, HER4 A Acrylamide adds to EGFR Cys797; shown by crystal structure or mass spectrometry CHEMBL1201129 Decitabine covalent broad Azacytosine nucleoside Protein cysteine Irreversible Other enzymes DNA methyltransferase 1 (DNMT1) A Incorporated into DNA, where the 5-aza ring traps the methyltransferase cysteine; shown by crystal structure CHEMBL1201229 Demecarium covalent broad Aryl carbamate Protein serine Slowly reversible Other enzymes Acetylcholinesterase (Ser203) B Carbamoylates the catalytic serine; the carbamoyl group hydrolyzes over minutes to hours CHEMBL1201863 Dexlansoprazole covalent broad Sulfinyl benzimidazole (prodrug) Protein cysteine Irreversible Transporters and pumps H+/K+ ATPase (gastric proton pump) A Acid converts the sulfoxide to a sulfenamide that forms a disulfide with luminal cysteines CHEMBL893 Dicloxacillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL2107333 Dimethyl fumarate covalent broad Fumarate Michael acceptor Protein cysteine Irreversible Small GTPases and other proteins KEAP1 (Cys151), activating NRF2 A Succinates KEAP1 cysteines; found empirically, mechanism worked out later CHEMBL3989944 Diroximel fumarate covalent broad Fumarate Michael acceptor Protein cysteine Irreversible Small GTPases and other proteins KEAP1 (Cys151), activating NRF2 B Prodrug of monomethyl fumarate CHEMBL1199307 Distigmine covalent broad Aryl carbamate Protein serine Slowly reversible Other enzymes Acetylcholinesterase (Ser203) B Carbamoylates the catalytic serine; the carbamoyl group hydrolyzes over minutes to hours CHEMBL964 Disulfiram covalent broad Disulfide Protein cysteine Irreversible Other enzymes Aldehyde dehydrogenase (ALDH2 Cys302) A Metabolite carbamoylates the catalytic cysteine CHEMBL491571 Doripenem covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL4298137 Durlobactam covalent strict Diazabicyclooctane Protein serine Reversible Bacterial cell-wall enzymes Beta-lactamases A Same carbamoylation mechanism as avibactam CHEMBL1200969 Dutasteride not_covalent none Slow-binding; any covalent adduct is with NADPH, a freely dissociating coenzyme CHEMBL1201341 Echothiophate covalent broad Organophosphate Protein serine Irreversible Other enzymes Acetylcholinesterase (Ser203) A Phosphorylates the catalytic serine CHEMBL830 Eflornithine covalent strict Enzyme-activated inactivator Protein cysteine Irreversible Other enzymes Ornithine decarboxylase A Designed suicide substrate that alkylates Cys360 after decarboxylation; shown by crystal structure CHEMBL4458276 Enmetazobactam covalent strict Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Beta-lactamases A Penicillanic acid sulfone acylates the catalytic serine and rearranges to a stable adduct; designed as a beta-lactamase inactivator CHEMBL953 Entacapone not_covalent none Nitrocatechol with a conjugated nitrile; reversible COMT inhibitor CHEMBL1174 Eptifibatide not_covalent none Cyclic peptide held by a disulfide; no covalent action CHEMBL1359 Ertapenem covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201320 Esomeprazole covalent broad Sulfinyl benzimidazole (prodrug) Protein cysteine Irreversible Transporters and pumps H+/K+ ATPase (gastric proton pump) A Acid converts the sulfoxide to a sulfenamide that forms a disulfide with luminal cysteines CHEMBL1756 Estramustine phosphate not_covalent none Carbamate is stable; acts on microtubules and the estrogen receptor, not as an alkylator CHEMBL456 Ethacrynic acid not_covalent none Michael acceptor that reacts with thiols, but covalent binding to NKCC2 is not established CHEMBL1441 Ethionamide not_covalent none Metabolite forms an adduct with NAD, a freely dissociating coenzyme CHEMBL1779710 Evogliptin not_covalent none Non-covalent DPP-4 inhibitor CHEMBL1200374 Exemestane covalent broad Enzyme-activated inactivator Protein residue (not assigned) Irreversible Other enzymes Aromatase (CYP19A1) B Steroidal mechanism-based inactivator; label describes irreversible binding; residue not firmly assigned CHEMBL1138 Ezetimibe not_covalent none Azetidinone that binds the NPC1L1 sterol transporter non-covalently CHEMBL710 Finasteride not_covalent none Forms an NADP-dihydrofinasteride adduct with the coenzyme, not with the protein CHEMBL917 Floxuridine covalent broad Fluoropyrimidine Protein cysteine Irreversible Other enzymes Thymidylate synthase (Cys195) A Metabolite FdUMP forms a covalent ternary complex with thymidylate synthase and folate; shown by crystal structure CHEMBL185 Fluorouracil covalent broad Fluoropyrimidine Protein cysteine Irreversible Other enzymes Thymidylate synthase (Cys195) A Metabolite FdUMP forms a covalent ternary complex with thymidylate synthase and folate; shown by crystal structure CHEMBL1308 Fomepizole not_covalent none Competitive alcohol dehydrogenase inhibitor CHEMBL4802240 Foscarbidopa not_covalent none Hydrazine forms a hydrazone with PLP cofactor (prodrug of carbidopa) CHEMBL1757 Fosfomycin covalent broad Epoxide Protein cysteine Irreversible Bacterial cell-wall enzymes MurA (UDP-N-acetylglucosamine enolpyruvyl transferase) A Epoxide alkylates the active-site Cys115; shown by crystal structure; natural product CHEMBL1103 Furazolidone not_covalent none Reactive nitroreduction metabolites act on many targets; no defined target bond CHEMBL3701238 Futibatinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases FGFR1-4 A Acrylamide adds to FGFR2 Cys491; shown by crystal structure or mass spectrometry CHEMBL1201116 Hetacillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL467 Hydroxyurea not_covalent none Quenches a tyrosyl radical of ribonucleotide reductase; no covalent bond to the target CHEMBL1873475 Ibrutinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases BTK A Acrylamide adds to BTK Cys481; shown by crystal structure or mass spectrometry CHEMBL1024 Ifosfamide covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; liver activation releases the mustard CHEMBL148 Imipenem anhydrous covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL92401 Iproniazid covalent broad Hydrazine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) B Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL1201168 Isocarboxazid covalent broad Hydrazine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) B Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL1025 Isoflurophate covalent broad Organophosphate Protein serine Irreversible Other enzymes Acetylcholinesterase (Ser203) A Phosphorylates the catalytic serine CHEMBL64 Isoniazid not_covalent none Metabolite forms an adduct with NAD, a freely dissociating coenzyme CHEMBL3545432 Ixazomib citrate covalent strict Boronic acid Protein threonine Reversible Proteases 26S proteasome (beta-5 subunit) A Boronic acid adduct with Thr1; prodrug of ixazomib CHEMBL480 Lansoprazole covalent broad Sulfinyl benzimidazole (prodrug) Protein cysteine Irreversible Transporters and pumps H+/K+ ATPase (gastric proton pump) A Acid converts the sulfoxide to a sulfenamide that forms a disulfide with luminal cysteines CHEMBL4558324 Lazertinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR A Acrylamide adds to EGFR Cys797; shown by crystal structure or mass spectrometry CHEMBL237500 Linagliptin not_covalent none Non-covalent DPP-4 inhibitor CHEMBL514 Lomustine covalent broad Nitrosourea DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; chloroethylation of guanine O6 and interstrand crosslinks CHEMBL1013 Loracarbef anhydrous covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL4297516 Lurbinectedin covalent broad Carbinolamine alkylator DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; minor-groove guanine N2 adduct CHEMBL1200468 Malathion covalent broad Organophosphate Protein serine Irreversible Other enzymes Acetylcholinesterase (Ser203) B Phosphorylates the catalytic serine; works through its oxon metabolite on the louse enzyme CHEMBL1909283 Mebanazine covalent broad Hydrazine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) B Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL427 Mechlorethamine covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; aziridinium ion crosslinks guanines CHEMBL852 Melphalan covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; aziridinium ion crosslinks guanines CHEMBL4303060 Melphalan flufenamide covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; peptide-conjugated melphalan CHEMBL127 Meropenem covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1201270 Methenamine not_covalent none Releases formaldehyde, which reacts with many biomolecules; no defined target CHEMBL575 Methicillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL416 Methoxsalen covalent broad Psoralen (photoactivated) DNA Irreversible DNA DNA pyrimidines A UVA light drives a cycloaddition to thymine that forms interstrand crosslinks CHEMBL137 Metronidazole not_covalent none Radical anion damages DNA; no defined covalent adduct on a target CHEMBL1731 Mezlocillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL105 Mitomycin covalent broad Aziridine DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; reductive activation, DNA crosslinks CHEMBL4650319 Mobocertinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR exon 20 insertions A Acrylamide adds to EGFR Cys797; shown by crystal structure or mass spectrometry CHEMBL589586 Monomethyl fumarate covalent broad Fumarate Michael acceptor Protein cysteine Irreversible Small GTPases and other proteins KEAP1 (Cys151), activating NRF2 A Active metabolite of dimethyl fumarate; same cysteine succination CHEMBL787 Montelukast not_covalent none Receptor antagonist CHEMBL74632 Moxalactam covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1443 Nafcillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL267495 Nalfurafine not_covalent none Unsaturated amide in a morphinan; opioid receptor agonist CHEMBL278020 Neostigmine covalent broad Aryl carbamate Protein serine Slowly reversible Other enzymes Acetylcholinesterase (Ser203) A Carbamoylates the catalytic serine; the carbamoyl group hydrolyzes over minutes to hours CHEMBL180022 Neratinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR, HER2 A Acrylamide adds to EGFR Cys797 and HER2 Cys805; shown by crystal structure or mass spectrometry CHEMBL1256841 Nialamide covalent broad Hydrazine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) B Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL4802135 Nirmatrelvir covalent strict Nitrile Protein cysteine Reversible Proteases SARS-CoV-2 main protease (Cys145) A Nitrile forms a thioimidate with the catalytic Cys145; shown by crystal structure CHEMBL1337 Nitisinone not_covalent none Tight-binding HPPD inhibitor; no covalent bond CHEMBL572 Nitrofurantoin not_covalent none Reactive nitroreduction metabolites act on many targets; no defined target bond CHEMBL3786343 Olmutinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR A Acrylamide adds to EGFR Cys797; shown by crystal structure or mass spectrometry CHEMBL4303525 Omaveloxolone covalent strict Cyanoenone Protein cysteine Reversible Small GTPases and other proteins KEAP1 (Cys151), activating NRF2 B Synthetic triterpenoid built around a cyanoenone Michael acceptor; KEAP1 Cys151 adduct shown for the class CHEMBL1503 Omeprazole covalent broad Sulfinyl benzimidazole (prodrug) Protein cysteine Irreversible Transporters and pumps H+/K+ ATPase (gastric proton pump) A Acid converts the sulfoxide to a sulfenamide that forms a disulfide with luminal cysteines CHEMBL175247 Orlistat covalent broad Beta-lactone Protein serine Irreversible Other enzymes Gastric and pancreatic lipase A Beta-lactone acylates the catalytic serine; derived from the natural product lipstatin CHEMBL3353410 Osimertinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases EGFR A Acrylamide adds to EGFR Cys797; shown by crystal structure or mass spectrometry CHEMBL819 Oxacillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1372 Oxiglutatione not_covalent none Oxidized glutathione; redox substrate CHEMBL1231 Oxybutynin not_covalent none Alkyne is not a warhead; muscarinic antagonist CHEMBL483254 Panobinostat not_covalent none Acrylamide-like hydroxamic acid that chelates zinc CHEMBL1502 Pantoprazole covalent broad Sulfinyl benzimidazole (prodrug) Protein cysteine Irreversible Transporters and pumps H+/K+ ATPase (gastric proton pump) A Acid converts the sulfoxide to a sulfenamide that forms a disulfide with luminal cysteines CHEMBL673 Pargyline covalent broad Propargylamine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) A Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL29 Penicillin g covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL615 Penicillin v covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1089 Phenelzine covalent broad Hydrazine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) A Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL753 Phenoxybenzamine covalent broad Haloalkylamine (aziridinium) Protein residue (not assigned) Irreversible GPCRs Alpha-adrenergic receptors B Forms an aziridinium ion that alkylates the receptor; the residue is not firmly assigned CHEMBL1909286 Phenoxypropazine covalent broad Hydrazine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) B Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL94 Physostigmine covalent broad Aryl carbamate Protein serine Slowly reversible Other enzymes Acetylcholinesterase (Ser203) A Carbamoylates the catalytic serine; the carbamoyl group hydrolyzes over minutes to hours CHEMBL702 Piperacillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL1585 Pipobroman covalent broad Bromoalkyl amide DNA Irreversible DNA DNA (guanine) B DNA alkylating agent; alkylating agent per ChEMBL CHEMBL4650485 Pirtobrutinib not_covalent none Non-covalent BTK inhibitor CHEMBL3182343 Pivampicillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL167731 Pixantrone not_covalent none Topoisomerase II poison and intercalator; formaldehyde-mediated DNA adducts are minor CHEMBL21333 Pranlukast not_covalent none Receptor antagonist CHEMBL1201772 Prasugrel covalent broad Thienopyridine (prodrug) Protein cysteine Irreversible GPCRs P2Y12 receptor A Liver metabolite thiol forms a disulfide with extracellular P2Y12 cysteines CHEMBL1321 Procarbazine covalent broad Methylating triazene or hydrazine DNA Irreversible DNA DNA (guanine) B DNA alkylating agent; methylates guanine O6 and N7 after activation CHEMBL1200627 Propiolactone not_covalent none Alkylating sterilant; no defined therapeutic target CHEMBL1115 Pyridostigmine covalent broad Aryl carbamate Protein serine Slowly reversible Other enzymes Acetylcholinesterase (Ser203) A Carbamoylates the catalytic serine; the carbamoyl group hydrolyzes over minutes to hours CHEMBL488093 Pyritinol not_covalent none Disulfide of pyridoxine; no covalent target action CHEMBL1219 Rabeprazole covalent broad Sulfinyl benzimidazole (prodrug) Protein cysteine Irreversible Transporters and pumps H+/K+ ATPase (gastric proton pump) A Acid converts the sulfoxide to a sulfenamide that forms a disulfide with luminal cysteines CHEMBL887 Rasagiline covalent broad Propargylamine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) A Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL3112741 Relebactam anhydrous covalent strict Diazabicyclooctane Protein serine Reversible Bacterial cell-wall enzymes Beta-lactamases A Same carbamoylation mechanism as avibactam CHEMBL4085457 Ritlecitinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases JAK3 A Acrylamide adds to JAK3 Cys909; shown by crystal structure or mass spectrometry CHEMBL163 Ritonavir not_covalent none Therapeutic target HIV protease is inhibited non-covalently CHEMBL636 Rivastigmine covalent broad Aryl carbamate Protein serine Slowly reversible Other enzymes Acetylcholinesterase (Ser203) A Carbamoylates the catalytic serine; the carbamoyl group hydrolyzes over minutes to hours CHEMBL343448 Romidepsin not_covalent none Disulfide prodrug; the reduced thiol binds zinc CHEMBL385517 Saxagliptin anhydrous covalent strict Nitrile Protein serine Reversible Proteases DPP-4 A Cyanopyrrolidine forms an imidate with Ser630; shown by crystal structure CHEMBL972 Selegiline covalent broad Propargylamine Prosthetic group (FAD) of target Irreversible Other enzymes Monoamine oxidase (FAD cofactor) A Oxidized by the enzyme to a species that binds the flavin, which is bound to the enzyme CHEMBL3545185 Selinexor covalent strict Acrylamide Protein cysteine Reversible Small GTPases and other proteins XPO1 (exportin-1) A Michael acceptor binds XPO1 Cys528; shown by crystal structure; the bond slowly reverses CHEMBL1422 Sitagliptin not_covalent none Non-covalent DPP-4 inhibitor CHEMBL4535757 Sotorasib covalent strict Acrylamide Protein cysteine Irreversible Small GTPases and other proteins KRAS G12C A Acrylamide adds to mutant Cys12 of KRAS; shown by crystal structure CHEMBL1977579 Streptozocin covalent broad Nitrosourea DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; methylation of guanine CHEMBL403 Sulbactam covalent strict Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Beta-lactamases A Penicillanic acid sulfone acylates the catalytic serine and rearranges to a stable adduct; designed as a beta-lactamase inactivator CHEMBL2104910 Sulfadicramide not_covalent none Sulfonamide antibacterial; the unsaturated amide is not reactive in this setting CHEMBL4594246 Sulopenem etzadroxil covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL443052 Tavaborole covalent broad Boronic acid RNA (tRNA terminus) Reversible Other enzymes Leucyl-tRNA synthetase (editing site) A Oxaborole forms a cyclic adduct with the 3-terminal ribose of tRNA-Leu, trapping it in the editing site; shown by crystal structure CHEMBL404 Tazobactam covalent strict Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Beta-lactamases A Penicillanic acid sulfone acylates the catalytic serine and rearranges to a stable adduct; designed as a beta-lactamase inactivator CHEMBL20883 Tegafur covalent broad Fluoropyrimidine Protein cysteine Irreversible Other enzymes Thymidylate synthase (Cys195) A Metabolite FdUMP forms a covalent ternary complex with thymidylate synthase and folate; shown by crystal structure; prodrug of 5-FU CHEMBL231813 Telaprevir covalent strict Ketoamide Protein serine Reversible Proteases HCV NS3/4A protease A Alpha-ketoamide forms a hemiketal with the catalytic serine; shown by crystal structure CHEMBL810 Temozolomide covalent broad Methylating triazene or hydrazine DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; methylates guanine O6 and N7 after activation CHEMBL2147777 Teneligliptin not_covalent none Non-covalent DPP-4 inhibitor CHEMBL17157 Terfenadine not_covalent none Receptor antagonist CHEMBL973 Teriflunomide not_covalent none Cyanoenol that binds DHODH reversibly CHEMBL671 Thiotepa covalent broad Aziridine DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; aziridine rings alkylate guanine N7 CHEMBL398435 Ticagrelor not_covalent none Reversible P2Y12 antagonist CHEMBL1449 Ticarcillin covalent broad Beta-lactam Protein serine Irreversible Bacterial cell-wall enzymes Penicillin-binding proteins A Beta-lactam acylates the transpeptidase serine; shown by crystal structure for penicillins and cephalosporins CHEMBL833 Ticlopidine covalent broad Thienopyridine (prodrug) Protein cysteine Irreversible GPCRs P2Y12 receptor B Same thienopyridine mechanism as clopidogrel; active metabolite less well characterized CHEMBL1314 Tiopronin not_covalent none Thiol that forms a soluble cystine mixed disulfide; no protein target CHEMBL4071161 Tirabrutinib covalent strict Butynamide Protein cysteine Irreversible Protein kinases BTK A Alkynamide adds to BTK Cys481; shown by crystal structure CHEMBL450449 Trabectedin covalent broad Carbinolamine alkylator DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; minor-groove guanine N2 adduct CHEMBL1650443 Trelagliptin not_covalent none Benzonitrile; non-covalent DPP-4 inhibitor CHEMBL455186 Treosulfan covalent broad Alkyl sulfonate DNA Irreversible DNA DNA (guanine) B DNA alkylating agent; epoxide metabolites crosslink DNA CHEMBL1129 Trifluridine covalent broad Fluoropyrimidine Protein cysteine Irreversible Other enzymes Thymidylate synthase B Monophosphate binds thymidylate synthase covalently; DNA incorporation also contributes CHEMBL1475 Trioxsalen covalent broad Psoralen (photoactivated) DNA Irreversible DNA DNA pyrimidines A UVA light drives a cycloaddition to thymine that forms interstrand crosslinks CHEMBL1488 Uracil mustard covalent broad Nitrogen mustard DNA Irreversible DNA DNA (guanine) A DNA alkylating agent; aziridinium ion crosslinks guanines CHEMBL3317857 Vaborbactam covalent strict Boronic acid Protein serine Reversible Bacterial cell-wall enzymes Beta-lactamases (KPC) A Cyclic boronate forms a tetrahedral adduct with the catalytic serine; shown by crystal structure CHEMBL89598 Vigabatrin covalent strict Enzyme-activated inactivator Protein lysine Irreversible Other enzymes GABA aminotransferase A Designed mechanism-based inactivator; covalent adduct with active-site Lys329; shown by crystal structure CHEMBL142703 Vildagliptin covalent strict Nitrile Protein serine Reversible Proteases DPP-4 A Cyanopyrrolidine forms an imidate with Ser630; shown by crystal structure CHEMBL2079130 Vonoprazan not_covalent none Potassium-competitive acid blocker; reversible CHEMBL4101807 Voxelotor covalent strict Aldehyde Protein N-terminus Reversible Small GTPases and other proteins Hemoglobin (alpha-chain Val1) A Aldehyde forms a Schiff base with the N-terminal valine; shown by crystal structure; withdrawn in 2024 CHEMBL1464 Warfarin not_covalent none Reversible inhibitor of VKORC1 CHEMBL603 Zafirlukast not_covalent none Receptor antagonist CHEMBL3936761 Zanubrutinib covalent strict Acrylamide Protein cysteine Irreversible Protein kinases BTK A Acrylamide adds to BTK Cys481; shown by crystal structure or mass spectrometry