There are a number of covalent modifiers in preclinical or early clinical investigation that will continue to offer insight to this drug discovery strategy, including ones that target the caspases,69 MMP13,70 thyroid hormone receptor,71 and FAAH.72
Certainly, the presence of small screening or fragment sets comprising compounds with low to moderately reactive functionality will be crucial for providing starting points. Alternatively, one could look to strategically position a warhead within a lead compound. Hopefully, the compilation of examples in this review will inspire drug discovery scientists to consider pursuing covalent modifiers in the future.
1.1.2 From reactants to drugs.
1.2 Covalent modifiers.
In most instances this has not been the strategy but rather discovered in hindsight.
Development of highly potent and selective covalent cysteine-protease inhibitors showed that many chemically different warheads are able to react with specific catalytic or non-catalytic cysteine residues in cysteine-protease active sites by covalent interaction. [5]
The Cysteine-trapping warheads described in the literature can be classified on the basis of their "cysteine interaction" mechanism:
alkylating warheads. [6]
Nucleophile substitution-based warheads.
Michael addition-based warheads.
Acylating warheads (as ï¢-lactons [7] and ï¢-lactams).
disulfide bond forming warheads. [8]
covalent but reversible warheads: an example of this kind of warhead can be represented by N-Cyanomethylamides that are able to covalently interact with a cysteine group on the target, forming a reversible thioimidate complex.
The covalent inhibition of a biological target (i.e. a receptor or an enzyme) presents some advantages with respect to the reversible one. Indeed, an irreversible inhibitor doesn't need prolonged circulating blood levels to achieve a desired biological effect. Once the target is deactivated by covalent bond formation, the biological effect should persist even after the drug leaves the circulation. As a result, the duration of action of such a drug will be long-lasting because will be a function of the rate of enzyme turnover.
However, the intrinsic reactivity of warheads often gives rise to low druggability of these molecules because they are often liable of a heavy metabolic degradation (low bioavailability) or toxicity for lack of target-specificity.
In order to overcome these drawbacks, two strategies could be used to improve the drug-likeliness of a reactive compound:
Modulate the "warhead" reactivity to decrease metabolic degradation and/or to optimize its selectivity.
Link the "warhead" fragment to "driver groups" that assure an increase of specificity by optimized fit at the active site of the target, in which the reactive centres are held in close proximity and proper orientation for a covalent interaction to ensue.
Both strategies have been used to develop cysteine-binder molecules that are still under investigation as cysteine-protease inhibitors or irreversible ligands of other cysteine-exposing targets.
Among covalent cysteine-protease inhibitors, some compounds have reached preclinical and clinical phases demonstrating that reactive warheads can be inserted in drug-like compounds. Presently, cathepsine inhibitors as APC-3328 or CRA-013783 have reached the preclinical phase as promising anti-osteoporosis drugs, while calpain inhibitor A-705253 and caspase-1 inhibitor Vx-765 are still under evaluation respectively as neuroprotecive and anti-inflammatory agents (Figure 1).
Figure 1
It is possible to change the target selectivity of synthesized cysteine-reactive compounds.
1.2.1 Warhead reactivity and target selectivity.
1.2.2 Serine and Tyrosine reactive compounds.
1.2.3 Cysteine reactive compounds.
Pharmacologically important target for cysteine-trapping agents
伦敦论文代写 生物学论文 Examining The Covalent Modifier In Drug Discovery
