Allosteric Inhibitor

Allosteric Inhibitor designates a molecule binding to a protein at a site distinct from the active or orthosteric site, inducing conformational changes that reduce catalytic activity, alter substrate binding, or modify protein-protein interactions through indirect mechanisms rather than direct competition with natural ligands or substrates.

The biopharmaceutical industry increasingly develops allosteric inhibitors for targets where orthosteric site inhibition proves challenging due to high substrate concentrations, poor selectivity within protein families, or lack of suitable binding pockets. Allosteric sites offer improved selectivity as they are often unique to specific protein family members. MEK inhibitors exemplify successful allosteric kinase inhibition achieving selectivity not possible with ATP-competitive approaches. KRAS G12C inhibitors bind an allosteric pocket present only in the mutant protein enabling tumour-selective targeting. Computational structure-based approaches identify cryptic allosteric pockets not visible in crystal structures. As understanding of protein conformational dynamics improves, allosteric inhibitor discovery continues expanding the druggable proteome.