Covalent, Non-covalent, and Covalent Reversible Drug Design in Medicinal Chemistry

Covalent, Non-covalent, and Covalent Reversible Drug Design in Medicinal Chemistry

Chemical drugs can be classified into three categories based on their binding modes: covalent drugs, non-covalent drugs, and covalent reversible drugs. Covalent drugs have strong binding ability and high efficacy, but they also come with strong toxic side effects. Non-covalent drugs have generally weaker binding ability, shorter duration of action, and relatively milder toxic side effects. Covalent reversible drugs, positioned between the other two categories, are considered relatively ideal, although their types are limited. Now, let’s discuss and summarize the chemical structures of these different types of drugs.

Covalent Drugs

Covalent drugs are primarily designed for amino acids with thiol or hydroxyl groups, such as cysteine, lysine, and serine. Well-known examples of covalent drugs include aspirin and penicillin (Fig. 1). The development of most covalent drugs involves intentionally introducing covalent bonding moieties that can interact with the target. Acrylamide is the most commonly used moiety, while epoxyethane and ethylene sulfonylamide are also common groups. The electrophilic groups on these drug molecules can undergo electrophilic-nucleophilic reactions with nucleophilic groups on the receptor, such as thiol, hydroxyl, amino, and imidazole groups, forming covalent bonds and achieving a higher level of receptor binding.

Structure of Penicillin
Fig. 1 Structure of Penicillin

A recently popular covalent drug is ibrutinib. Ibrutinib is an anti-tumor drug that inhibits the proliferation and survival of malignant B cells in vivo and the migration of cells in vitro, thereby inhibiting tumor growth.

Structure of Ibrutinib
Fig. 2 Structure of Ibrutinib

Non-covalent Drugs

Non-covalent drugs constitute the largest category of chemical drugs today, such as imatinib. Non-covalent drugs generally lack structures like unsaturated acrylamide and do not possess electrophilic properties. Traditional drug molecules, for the most part, are non-covalent drugs, and the forces of interaction between them and receptors are typically non-covalent, such as hydrogen bonding and dipole-dipole interactions.

Structure of Imatinib
Fig. 3 Structure of Imatinib

At the beginning of the new year, the FDA approved Loxo’s pirtobrutinib for the treatment of relapsed or refractory mantle cell lymphoma (MCL) in adult patients. Pirtobrutinib is a third-generation BTK inhibitor and the first non-covalent BTK inhibitor.

Structure of pirtobrutinib
Fig. 4 Structure of pirtobrutinib

Chemicals at BOC Sciences

NameCASMFMW
Aspirin50-78-2C9H8O4180.16
Penicillin525-94-0C14H21N3O6S359.40
Penicillin G61-33-6C16H18N2O4S334.39
Penicillin V87-08-1C16H18N2O5S350.4
(S)-Ibrutinib936563-97-2C25H24N6O2440.51
Pirtobrutinib2101700-15-4C22H21F4N5O3479.4
Saxagliptin361442-04-8C18H25N3O2315.417
Telaprevir402957-28-2C36H53N7O6679.85
Boceprevir394730-60-0C27H45N5O5519.687
Narlaprevir865466-24-6C36H61N5O7S707.96
Bortezomib179324-69-7C19H25BN4O4384.24
Ixazomib1072833-77-2C14H19BCl2N2O4361.026
Voxelotor1446321-46-5C19H19N3O3337.37

Covalent Reversible Drugs

Common covalent reversible structures include carbonyl, cyanide, boronic acid, and so on (see Fig. 5).

Common covalent reversible structures (Faridoon, Ng R, et al. 2023)
Fig. 5 Common covalent reversible structures (Faridoon, Ng R, et al. 2023)

Alpha-cyanoacrylamide is a recently reported covalent reversible structure. This structure was first reported by Jack Taunton, who used a reversibly covalent inhibitor to target non-catalytic cysteine in Bruton’s tyrosine kinase, employing a reverse-oriented electrophilic reagent with cysteine-reactive cyanide acrylamide. The biochemical half-life of this structure ranges from minutes to 7 days. In vivo, the reverse cyanoacrylamide remains bound to proteins for over 18 hours after removal from circulation. This reverse cyanoacrylamide strategy has been further applied to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with several days of residence time, demonstrating the method’s generality.

Recently, Reja R M and others developed a new reversible lysine binder, characterized by new dinitrogen borane products and much slower dissociation kinetics compared to previously known subaminoboronic acid salts. Attaching the dinitrogen hetero-borane head RMR1 to a peptide ligand produces a potent and long-lasting reversible covalent inhibitor of staphylococcal sortase enzymes.

Conditionally reversible covalent inhibitors are also a new idea. The human body is a vast chemical reaction library, and various chemical reactions occur every day. A covalent inhibitor, under the influence of the body’s chemical reaction library, achieves a reversible effect. This design concept is a new way to design covalent compounds that degrade in the body’s chemical environment, similar to the design concept of prodrugs.

Rererences

  1. Kim H , Hwang Y S , Kim M , et al. Recent advances in the development of covalent inhibitors[J]. RSC Medicinal Chemistry, 2021, 12(7):1037-1045.       
  2. Faridoon, Ng R, Zhang G, et al. An update on the discovery and development of reversible covalent inhibitors[J]. Medicinal Chemistry Research, 2023: 1-24.       
  3. J Michael Bradshaw , Jesse M McFarland , Ville O Paavilainen , Angelina Bisconte , Danny Tam , Vernon T Phan , Sergei Romanov , David Finkle , Jin Shu , Vaishali Patel , Tony Ton , Xiaoyan Li , David G Loughhead , Philip A Nunn , Dane E Karr , Mary E Gerritsen , Jens Oliver Funk , Timothy D Owens , Erik Verner , Ken A Brameld , Ronald J Hill , David M Goldstein , Jack Taunton. Prolonged and tunable residence time using reversible covalent kinase inhibitors,Nature Chemical Biology,2015,11:525-331.
  4. Reja R M, Wang W, Lyu Y, et al. Lysine-targeting reversible covalent inhibitors with long residence time[J]. Journal of the American Chemical Society, 2022, 144(3): 1152-1157.