Data-Driven Global Assessment of Protein Kinase Inhibitors with Emphasis on Covalent Compounds

Abstract

Large-scale analysis of public human and mouse protein kinase inhibitor (PKI) data identified more than 155,000 human PKIs (and ∼3000 murine PKIs), for which reliable activity measurements were available. Human PKIs were active against 440 kinases (85% coverage of the kinome). Over the past years, there has been substantial growth of human PKIs, dominated by inhibitors with single-kinase annotations and high core structure diversity. Human PKIs included an unexpectedly large number of nearly 14,000 covalent PKIs (CPKIs), ∼87% of which contained acrylamide or heterocyclic urea warheads. These CPKIs were active against a large number of 369 human kinases. The promiscuity of PKIs and CPKIs was overall comparable. However, there was a notable enrichment of acrylamide-but not heterocyclic ureacontaining CPKIs among most promiscuous inhibitors. Furthermore, CPKIs with both warheads had significantly higher potency than structurally analogous PKIs. Taken together, these findings have several implications for medicinal chemistry that are discussed.

Systematic Analysis of Covalent and Allosteric Protein Kinase Inhibitors

“…In a recent large-scale analysis, we identified 155,579 unique PKIs in public databases that were active against 440 human kinases on the basis of curated high-confidence activity data [9]. Rather unexpectedly, these PKIs were found to include 13,949 potential CPKIs that contained 13 commonly used warheads (the presence of a warhead does not necessarily lead to covalent PK inhibition).…”

“…Most PKIs bind to the ATP-binding pocket or proximal to it (type I, I1/2, or II). Considering the conservation of this site across the human kinome, multi-PK activity of ATP site-directed (type I) inhibitors is expected, but this is not generally the case [9,10]. Indeed, a variety of selective ATP site-directed PKIs have been reported [11,12].…”

“…Various warheads with different chemical properties are used for CPKIs, likely leading to different binding and inhibition characteristics, which are typically explored on a case-by-case basis for CPKIs of interest. In a recent systematic analysis of PKIs in public databases, an unexpectedly large number of nearly 14,000 CPKI candidates was identified that contained at least one of 13 commonly used warheads and were active against a total of 369 human kinases [9]. Acrylamide and heterocyclic urea were the most frequently occurring warheads, and CPKIs containing these two moieties were further analyzed.…”

“…They were found to have a generally higher potency than structural analogues without warheads. In addition, it was found that CPKIs with acrylamide, but not heterocyclic urea, were enriched among most promiscuous PKIs [9].…”

Landscape of In Silico Tools for Modeling Covalent Modification of Proteins: A Review on Computational Covalent Drug Discovery

“…Nevertheless, within the capacity of this review, it will be impossible to discuss all of the outstanding contributions in this research area. Thus, we refer the reader to a detailed list of references here. − Our review here starts with a brief discussion on the kinetics of covalent inhibition. It is then followed by discussion on different investigations classified based on the methods/approach considered (e.g., “reports focusing on p K a ’s of reacting amino acid residues”, “reports focusing on QM treatment of covalent fragment-adducts”, “reports focusing on determining the binding poses”, “reports focusing on the evaluation of binding free energies”, “reports focusing on determining the catalytic mechanism”, and “reports focusing on machine learning/artificial intelligence driven methodologies”).…”