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For the containment of proteins that play a key mediating role in disease formation, pharmacists usually use the means of synthesizing a drug molecule and "binding" it through non-covalent binding, causing it to undergo changes in spatial structure or other aspects and lose its pathological function, so as to achieve the ultimate goal of
curing the disease.
However, designing suitable drug molecular inhibitors is not a one-time thing, and the usual non-covalent bindings, including hydrogen bonding, ionic bonding, dipole-dipole interaction (van der Waals force), hydrophobicity, aromatic ring interaction, etc.
(Figure 1), cannot lock in the protein
once and for all.
The reason is that adsorption-desorption is a dynamic equilibrium process, and the drug molecules bound to the protein will be replaced by other molecules and released, thereby losing the restriction
on the pathogenic mechanism of the target protein.
Figure 1.
Common intermolecular non-covalent interactions (Credit: Chemical Reviews)
Based on the above considerations, pharmacists have adopted a more powerful drug molecular design concept - covalent bond drugs
.
As the name suggests, covalent drugs differ from conventional non-covalent drugs in that covalent drugs lose their pathogenic function
by forming stronger covalent bonds with specific proteins.
by forming stronger covalent bonds with specific proteins.
A covalent bond is a new chemical bond between two atoms that is created by averaging electrons (relatively average, a pair of shared electrons can be biased towards more electronegativity atoms, resulting in the polarity of the bond
, but covalent or covalent).
Although the formation and cleavage of covalent bonds is also an equilibrium process, compared to non-covalent bonds, once a new covalent bond is generated, the low energy in the system is not enough to cleave it, so it can exist
relatively stably.
relatively stable.
Adducts produced by covalently bonded drugs to proteins can be considered an irreversible process
to some extent.
Once formed, the protein-mediated pathogenic process is cut off and the causative process is terminated until the body produces the disease-mediating protein again, but this usually takes a few days to process
.
Therefore, covalently bonded drugs can produce longer duration of action and require lower
doses than non-covalently bonded drugs.
Based on these advantages, covalent bond drugs have gradually become the focus of
pharmaceutical companies in recent years.
This can be seen from the growth in the number of patents and documents for this class of drugs in recent years (Figure 2).
Figure 2.
Graph of changes in the number of patents and documents of covalent bond inhibitors (Source: CAS)
Covalent bond drugs are not actually emerging drugs, but this concept has not been valued and used
by the pharmaceutical industry until the last 20 years.
Aspirin, as it is commonly known as a covalent bonding drug, reacts with serine on the receptor enzyme in the body, causing serine to be acetylated and depriving the enzyme of its ability to catalyze inflammation and the formation of blood clotting molecules (Figure 3).
Therefore, aspirin was regarded as an anti-inflammatory, antipyretic and anti-thrombosis (thereby preventing myocardial infarction, stroke and angina) miracle drug
in that era.
Its essential mechanism of action is due to the reaction
of acetyl transfer.
Figure 3.
The mechanism behind aspirin's anti-inflammatory, anticoagulant covalent bond inhibition enzyme function
Although drugs that covalently bond with receptors have existed since the origins of the modern pharmaceutical industry, the exclusive study of such drugs is in a relatively recent time frame
.
In the past two decades, covalent bond drugs have developed
rapidly based on drug success cases such as the targeted anticancer drug irutinib (covalently bonded to bind and inhibit BTK Bruton-tyrosine kinase).
Figure 4 shows the famous covalent bond drugs
in the long history of drug development.
Among them, the red functional group/chemical structure is the active group in the drug, which is responsible for forming covalent bonds with the receptor protein and inhibiting its pathogenic mechanism
.
Some people may ask: Why does this drug contain highly active Michael addition reaction electrophilic receptors? Why is there such a highly reactive structure as ethoxy? Why are there aldehyde groups? Do they not affect the stability of the drug? In fact, the therapeutic mechanism of these seemingly unstable drugs may be achieved by the formation of
covalent bonds between these active functional groups and receptor proteins.
Figure 4.
Covalent bond drug development history
Although covalent bonded drugs have the advantages of long efficacy and low dose, there are still concerns that these active substances will indiscriminately bind to proteins in the body and cause various unexpected side effects, and at the same time, the immune response that these drugs may trigger is also their concern
.
Safety is therefore a top
priority in the covalent drug design and development process.
In the history of covalent bond drug development, irutinib is regarded as a landmark marketed drug
.
Ibrutinib, marketed under the name Imbruvica, inhibits Bruton's tyrosine kinase (BTK), an enzyme that is active in certain cancer cells, through a covalent reaction (Figure 5).
Ibrutinib was originally designed by Celera Genomics in 2005 as a tool to study the biology of BTK (it can be seen that at first, irutinib was not seriously treated as a lead drug).
Celera sold the compound as part of a package deal in 2006 to Pharmacyclics, which used the molecule for clinical development
.
.
Figure 5.
Schematic diagram of inhibition of BTK (Bruton tyrosine kinase) by the covalent bond inhibitor irutinib
Since irutinib was initially overlooked by many pharmaceutical practitioners, its success has sparked a revolution
in the way of thinking in the industry.
Many people assume that irutinib will be less selective based on its chemical structure alone, but the FDA approved the compound in 2013 for the treatment of cellular lymphoma, and now it is also used to treat five other cancers
.
This led people to reflect on their original judgments
.
Another interesting aspect of irutinib is that it generates great profits
.
Its success prompted AbbVie to pay $21 billion
for Pharmacyclics in 2015.
Ibrutinib is considered by some industry insiders to be the first magic molecule
to truly verify the value of covalent inhibitors.
The molecular design of covalently bonded drugs has also quietly changed
in the last 20 years.
In the first decade of the 21st century, pharmaceutical companies used the most common means in the development of covalently bonded drugs: adding active functional groups that can react with receptor proteins, such as acrylamide or chloroacetamide
, to the framework of non-covalent bonded drugs.
Although this method has not completely withdrawn from the historical stage, drug molecular designers no longer have to rely on reversible non-covalent bond drug modification to invent new covalent bond drugs
.
They can use a database of active fragments to screen receptors for effective binding and use this as a basis to design covalent bond inhibitors that react with receptors that do not have a molecular binding pocket and have traditionally been seen as a huge challenge in drug design, such as KRAS G12C
.
KRAS is a key protein
involved in the signaling process of cell division and proliferation.
But KRAS and its family members (whose mutants are present in 30 percent of cancers) had no obvious pocket binding site, and it took decades for drug developers to design a satisfactory non-covalently binding molecule
.
In 2013, a team led by Kevan Shokat of the University of California, San Francisco, discovered KRAS's mutant KRAS G12C, the 12th amino acid residue on the protein sequence that changes from glycine to cysteine
.
Shokat discovered that the sulfhydryl group of the cysteine side chain in KRAS G12C can be a target for drug covalent binding
.
Because this glycine mutation to cysteine occurs only in cancer cells, small molecule covalent bond drugs only specifically interact with KRAS G12C without affecting the regular KRAS protein
.
In the case of KRAS G12C, the acrylamide electrophile group on the drug molecule undergoes a michaelplus reaction
with the sulfhydryl group of cysteine.
But in particular, this reaction seems to take advantage of the catalysis
of lysine near cysteine on proteins.
Because when glycine at the 13th residue (the amino acid at position 13 also happens to be glycine) is replaced with cysteine, the resulting KRAS G13C variant is inactive against the same acrylamide drug molecule, which may be Lys' Neighbor effect at work
.
Encouraged by these data, the 12th cysteine on the KRAS G12C protein in cancer cells has become the focus of drug development, triggering a research boom
on covalent bonding drugs.
The clinical-stage KRAS G12C covalent inhibitor molecule and its receptor protein do not have a strong non-covalent binding force like traditional drugs, but when they are combined, the active group on the drug molecule quickly reacts
with Cys12 of KRAS G12C.
For example, Mirati Therapeutics' clinical drug MRTX849 (Adagrasib) (Figure 6).
Figure 6.
Crystal diagram
of the acrylamide group on the drug molecule MRTX849 (Adagrasib) after covalently binding to the Cys12 of the KRAS G12C protein (the yellow part on the crystal structure of the protein on the right is the sulfur atom on Cys).
(Image source: Journal of Medicinal Chemistry)
Acrylamide groups are electrophilic structures commonly used by covalent bonded drugs, and practitioners have studied their properties in the field of drug research and development most thoroughly
.
Ibrutinib, the MRTX849 (Adagrasib) mentioned above, and Sotorasib (Sotorasib), a drug launched last year for the treatment of KRAS G12C-mutated advanced or metastatic non-small cell lung cancer, all contain acrylamide structures
in their molecules.
There are also some covalently bonded drugs that do not take advantage of the acrylamide structure, such as Wanke, which relies on a reaction between its own boric acid group and the threonine on the receptor protein (Figure 4).
There is also the antibiotic drug fosfomycin, which mediates the reaction of ethoxy groups with cysteine (Figure 4).
In terms of protein receptors, the most widely studied and widely used amino acid is cysteine
.
Many covalently bonded drugs on the market use the reaction
between the electrophilic group of the drug molecule and the sulfhydryl group of cysteine of the protein receptor.
The sulfhydryl group of the deproton is highly nucleophilic and can react quickly with the electrophilic groups on drug molecules, such as acrylamide, so it is most favored
by drug developers.
The electrophilic groups of common covalently bonded drugs, as well as the amino acids on their corresponding receptor proteins, are systematically shown in
Figure 7.
Figure 7.
Covalently bonded drug electrophilic groups and receptor protein amino acid counterparts (Image source: ChemBioChem)
Although the emerging covalent bond drugs cannot become the mainstream of drug development in a short period of time, their boom has provided the pharmaceutical industry with new powerful tools
.
Table 1 summarizes the covalent bond drugs approved by the FDA from 2010 to 2019, and Table 2 partially shows the covalent drugs
currently in the clinical stage.
It is conceivable that with the continuous development of drug design, if covalent bond drugs can make breakthroughs in safety and specificity, they will have a revolutionary impact
on the pharmaceutical industry.
Table 1.
Covalent Bond Drugs Approved by the FDA Between 2011 and 2019 (Source: RSC Medicinal Chemistry)
References:
References:
[1] Jay B.
Fell, et al.
Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.
J.
Med.
Chem.
2020, 63, 6679–6693.
Fell, et al.
Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.
J.
Med.
Chem.
2020, 63, 6679–6693.
[2] Samuel E.
Dalton, Sebastien Campos.
Covalent Small Molecules as Enabling Platforms for Drug Discovery.
ChemBioChem, 2020, 21, 1080 –1100.
Dalton, Sebastien Campos.
Covalent Small Molecules as Enabling Platforms for Drug Discovery.
ChemBioChem, 2020, 21, 1080 –1100.
