Approved Covalent Drug Mechanisms

By Dennis Hu

It’s hard not to think about infectious diseases at the moment, but it’s a great time to review the drug discovery literature. One area of drug discovery that has deep roots in infectious disease research is targeted covalent inhibition. Targeted covalent inhibitors form covalent bonds with discrete targets (as opposed to non-specific modifiers like nitrogen mustards or nucleoside analogs like remdesivir which make covalent bonds while being incorporated into RNA or DNA). Here’s a visual summary of all of the unique mechanisms of targeted covalent inhibition among approved drugs, with each unique functional group exemplified by an arbitrarily chosen approved drug.

Acylation
Beta-lactam
Beta-lactone
carbomate
alkylester
hydroxycoumarin
thiocarbamate
Disulfide Bond Formation
sulfenamide
omeprazole
thiol
clopidogrel
thioselenide Formation
thiourea
propylthiouracil
selenocysteine conjugation
1,4 - Conjugate Addition 
acrylamide / alkynamide
afatinib
vinyl ketone
gemcitabine
flourouracil
floxuridine
Alkylation
aziridinium
phenoxybenzamine
epoxide
fosfomycin
1,2-Addition to sp2Atom
ketone
telapravir
aldehyde
voxelotor
triazinone
azacitidine
Metal Co-factor Binding
peroxyhemiacetal
exemstane
Boronation
boronic acid
bortezomib
Pinner Reaction
nitrile
saxagliptin
Co-factor Modification
PLP modification
vigabatrin
nicotinamide modification
finasteride

There’s a special place in my heart for covalent drugs, because they marry mechanistic organic chemistry with biochemistry in some amazing ways (the mechanism of omeprazole activation never gets old!). My first exposure to drug discovery as an undergraduate was through an amazing course taught by my chemistry major advisor called “The Organic Chemistry of Enzyme-Catalyzed Reactions.” Rick Silverman walked us through the mechanisms of deceptively simple looking inhibitors like vigabatrin, and emphasized how important it was to consider every residue involved in an enzymatic process, including general bases. You can imagine my surprise when I entered industry and discovered that covalent inhibition was something to be generally avoided.

Fortunately in the last several years there’s been a resurgence in interest in covalent inhibitors. If you’re like me and haven’t thought about covalent modifiers for a long time, here’s some suggested reading to help get quickly caught up on the field. These reviews cite pretty much anything else you’d need.

Reading List:

  1. The above graphic focuses on mechanisms of approved drugs, but there’s plenty of other covalent modifiers that don’t have approved examples yet. Here’s an excellent recent review on emerging warheads: Gehringer, M.; Laufer, S. A. “Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology.” J. Med. Chem. 2019, 62, 5673-5724.
  2. A nice tutorial review on targeted covalent inhibitors from AstraZeneca scientists: Lonsdale, R.; Ward, R. A. “Structure-based design of targeted covalent inhibitors.” Chem. Soc. Rev. 2018, 47, 3816.
  3. If you’re a kinetics nerd like me you’ll enjoy this review discussing the different classes of covalent inhibitors by mechanism: “The Taxonomy of Covalent Inhibitors.” Biochemistry, 2018, 57, 3326-3337.
  4. A recent high level overview on the resurgence of covalent drugs, with a nice table in the supporting information: Singh, J.; Petter, R. C.; Baillie, T. A., Whitty, A. “The resurgence of covalent drugs.Nature Rev. Drug. Discov. 2011, 10, 307-317.
  5. A now classic JMC on targeted covalent inhibitors with references on mechanisms: Potashman, M. H.; Duggan, M. E. “Covalent Modifiers: An Orthogonal Approach to Drug Design.” J. Med. Chem. 2009, 52, 1231-1246.

Enjoy, and stay safe while we’re practically “covalently attached” home!

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