Covalent inhibitors: a rational approach to drug discovery

Abstract

<p>In this review we provide a brief historic overview of covalent inhibitors and summarize recent advances focusing on developments in the last decade. Applications in challenging targets and future perspectives are also discussed.</p>

Fragment-based covalent ligand discovery

“…However, there has been a resurgence of interest in covalent inhibitors that has resulted in a host of new approaches for discovering and developing covalent inhibitors, resulting in 7 covalent drugs (from the total of 161 small molecule drugs) approved by the FDA from 2015 to 2019. 9 Rational covalent inhibitor design usually starts with a known noncovalent binder and explores strategies to incorporate an appropriate electrophilic warhead to achieve desired target selectivity and efficacy (''binder-first'' approaches). 2,3,10 While this approach has been successful, it is limited to targets that: (1) have existing ligands amenable to further derivatization with a reactive warhead; and (2) include a suitably reactive residue within or near the noncovalent ligand binding site.…”

Targeting the RdRp of Emerging RNA Viruses: The Structure-Based Drug Design Challenge

“…Obviously, they also have disadvantages, such as episodes of toxicity and hypersensitivity [87,91]. In the development of TCIs, the target's features should be thoroughly examined because not all the target proteins are suitable for this type of inhibition mechanism due to the high turn-over or degradation rate [92].…”

Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

“…Inhibitors which form a covalent bond to their targets are enjoying a resurgence because of their potential for longlasting effects and strong affinity for the target, amongst other benefits. [201][202][203][204][205][206][207] Indeed, around 30% of all approved clinical drugs acting on enzymes are covalent inhibitors. 202,207 Covalent inhibitors can cause either reversible or irreversible inhibition of their target.…”