An orthosteric site is commonly viewed as the primary, functionally binding pocket on a receptor. Signal molecules, endogenous agonists, and substrates are recognized by and bind to the orthosteric site of a specific target, resulting in a biological effect. A malfunctioning active site on a crucial receptor has been confirmed as the culprit that causes many metabolic disturbances, neurologic disorders, and genetic diseases. A competitive inhibitor that has a stronger binding affinity can outcompete an orthosteric ligand. An allosteric site, which is nonoverlapping and topographically distinct from the active pocket, can emerge as a potential regulatory site on the protein surface. An allosteric modulator interacts with a specific binding site, affecting the atoms of nearby residues, thus eliciting a series of conformational changes in the residues at the active site through propagation pathways. Allosteric regulation can potentiate or inhibit function instead of blocking it, and this is a promising strategy for drug design. In this chapter, we describe the tools and protocols for allosteric site analysis and allosteric ligand design.
Keywords: Allosteric site; Allostery; Computational methods; Drug design; Orthosteric site.