Orthosteric and allosteric modulation of human kinases: A mechanistic view

Abstract

Human kinases represent a large family of enzymes with their primary function being the phosphorylation of various biomolecules. Kinases along with G-Protein Coupled Receptors (GPCRs) represent wo of the most common protein targest in drug discovery. Kinases are classified by the substrate they phosphorylate namely, protein kinases, carbohydrate kinases and lipid kinases. These different classes have unique mechanism of action but show considerable overlap in their structural assembly and sequence of chemical modifications. Compounds can modulate kinadse activity by interacting with the enzyme's ATP binding site (orthostatic site) or the allosteric site. These modulators have been classified as Types I, II, III and IV depending on their mode of binding. Inclusion of atypical kinases and pseuokinases in the targetable kinome along with the recent approval of kinase-based therapeutics provides an impetus to the ever-growing field of kinase modulation. This review attempts to summarize the identification, historical stance, catalytic structure and subsequent development of kinases as significvant drug targets with an emphasis on their catalytic machinery and modulation.