Covalent Inhibition in Drug Discovery: Filling the Void in Literature

Abstract

The serendipitous discovery of covalent inhibitors and their characteristic potency of inducing irreversible and complete inhibition in therapeutic targets have caused a paradigm shift from the use of non-covalent drugs in disease treatment. This has caused a significant evolution in the field of covalent targeting to understand their inhibitory mechanisms and facilitate the systemic design of novel covalent modifiers for 'undruggable' targets. Computational techniques have evolved over the years and have significantly contributed to the process of drug discovery by mirroring the pattern of biological occurrences thereby providing insights into the dynamics and conformational transitions associated with biomolecular interactions. Moreover, our previous contributions towards the systematic design of selective covalent modifiers have revealed the various setbacks associated with the use of these conventional techniques in the study of covalent systems, hence there is a need for distinct approaches. In this review, we highlight the modifications and development of computational techniques suitable for covalent systems, their lapses, shortcomings and recent advancements.

Lysine Covalent Antagonists of Melanoma Inhibitors of Apoptosis Protein

“…Recently, several covalent agents targeting surface Cys residues have entered clinical studies in oncology. ,− Based on this success and expanding on the relatively limited target space of the Cysteinome, we and others propose the introduction of suitable electrophiles to target other residues. ,,,, Our own recent studies ,, and others , suggested that it is possible to target Lys residues located at protein–protein interfaces, in principle expanding the target space of covalent antagonists to protein–protein interactions (PPIs) that have a Lys in the vicinity of their binding sites. , We recently found that certain substituted aryl-sulfonyl fluorides, namely, as in compounds 1 or 2 (Table ), possess a more balanced reactivity and stability in aqueous buffer and in cell, and hence, they can be used as electrophiles in pharmacological tools and perhaps future therapeutics . These previous studies were conducted targeting the BIR3 domains of XIAP, cIAP1, or cIAP2.…”

Aryl-fluorosulfate-based Lysine Covalent Pan-Inhibitors of Apoptosis Protein (IAP) Antagonists with Cellular Efficacy

“…In recent years, we have witnessed a resurgence of targeted covalent therapeutics, with several newly covalent agents targeting surface Cys residues entering clinical studies. ,− Arguably, this success is attributable to the proper balance between Cys reactivity, plasma stability, and cell permeability of acrylamide warheads. α–β unsaturated carbonyls in acrylamides have been particularly attractive for cysteine drug targeting because of their balanced reactivity.…”

“…Covalent inhibitors targeting Cys residues have recently provided drug designers the ability to attain potent and selective irreversible inhibitors with proper pharmacological properties. Hence, the design of targeted irreversible inhibitors is currently heavily pursued, − and it has resulted in the recent FDA approval of several covalent drugs in oncology. Acrylamide-based Cys-covalent kinase inhibitors, osimertinib, ibrutinib, neratinib, and afatinib, for example, have all been approved by the FDA in very recent years, to cite a few.…”

A Mechanistic Study of a Potent and Selective Epidermal Growth Factor Receptor Inhibitor against the L858R/T790M Resistance Mutation

“…In this study, an in-house cMD simulation protocol was employed that has been validated as previously reported. ,− The Amber14-integrated particle mesh Ewald molecular dynamics (PMEMD) graphical processing unit (GPU) was used to perform the cMD simulations wherein the generalized AMBER force field “leap.gaff” was used to model the inhibitor ( 20g ), and the “leaprc.ff14SB” force field, the protein biomolecules. Moreover, the covalently linked 20g -Cys797 was parametrized using the integrated Antechamber module, and the Link, Edit, and Parm (LEaP) module was used to create a library for the covalent binder.…”