Image: By Boghog2 - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7078192
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.
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.
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.
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.
Fig. 4 Structure
of pirtobrutinib
Covalent Reversible Drugs
Common covalent reversible structures
include carbonyl, cyanide, boronic acid, and so on (see Fig. 5).
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
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.
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.
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.
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.
Author:
Carrier Taylor
R & D Director and Business Development
Director of BOCSCI
2014 - Present, working in BOCSCI
2012-2014 Study in Rice University, MBA
2004-2008 Study in Rice
University,Pharmacy
Linkedin profile: https://www.linkedin.com/in/carrier-taylor/
Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)