Multifaceted Small Molecules as Enzyme Modulators: Cases of Drug Discovery/Repurposing Illustrating Nature′s Pragmatism

The cross-reactivity of substrates, modulators with other enzymes significantly reduces/prevents our ability to design such highly specific, that is, "one warhead-one target", modulators. On the other hand, the potential "impasse" fuels repurposing of already developed drugs. Additionally, expanding our understanding that there will be "off-target" effects for enzymes of different evolutionary kingdoms propels the development of covalent reversible drugs. In this review/perspective, we examine these challenges and opportunities based on covalent drugs used/developed for targeting bacterial and mammalian enzymes, and our evolving understanding of the blurred difference between these enzymes in these "vastly" separated organisms by biological evolution.