Use of Allosteric Targets in the Discovery of Safer Drugs

Abstract

The need for drugs with fewer side effects cannot be overemphasized. Today, most drugs modify the actions of enzymes, receptors, transporters and other molecules by directly binding to their active (orthosteric) sites. However, orthosteric site configuration is similar in several proteins performing related functions and this leads to a lower specificity of a drug for the desired protein. Consequently, such drugs may have adverse side effects. A new basis of drug discovery is emerging based on the binding of the drug molecules to sites away (allosteric) from the orthosteric sites. It is possible to find allosteric sites which are unique and hence more specific as targets for drug discovery. Of many available examples, two are highlighted here. The first is caloxins - a new class of highly specific inhibitors of plasma membrane Ca²⁺ pumps. The second concerns the modulation of receptors for the neurotransmitter acetylcholine, which binds to 12 types of receptors. Exploitation of allosteric sites has led to the discovery of drugs which can selectively modulate the activation of only 1 (M1 muscarinic) out of the 12 different types of acetylcholine receptors. These drugs are being tested for schizophrenia treatment. It is anticipated that the drug discovery exploiting allosteric sites will lead to more effective therapeutic agents with fewer side effects.

Structure-based discovery of selective positive allosteric modulators of antagonists for the M 2 muscarinic acetylcholine receptor

“…To overcome intrafamily promiscuity of mAChR orthosteric drugs, investigators have begun to target the allosteric sites of these receptors ( 10 , 11 ). The best-established of these sites, first identified by functional pharmacology ( 12 – 16 ), have recently been structurally characterized by crystallography ( 17 ) and are now known to atomic resolution for most mAChR subtypes (M 1 –M 4 ) ( 17 – 19 ).…”

Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites

“…Recent studies have demonstrated the improved drugability of the allosteric binding sites of PTP1B as compared to its catalytic/active site . Allosteric sites have higher specificity, novel modes of efficacy, lower toxicity, and fewer side effects compared to the evolutionarily conserved active sites . We have identified and validated three novel binding sites/pockets on PTP1B that are distal from the active site.…”

Allosteric binding sites in Rab11 for potential drug candidates

“…Targeting these active sites has the drawbacks such as unwanted side-effects, lack of efficacy and poor selectivity [ 112 ]. One solution to this problem is to design drugs that target allosteric sites in proteins [ 113 ]. Allosteric drugs work by stabilizing a unique conformation of protein and either activating or inhibiting the reactions carried out at the active site [ 113 ][ 114 ].…”

“…One solution to this problem is to design drugs that target allosteric sites in proteins [ 113 ]. Allosteric drugs work by stabilizing a unique conformation of protein and either activating or inhibiting the reactions carried out at the active site [ 113 ][ 114 ]. Moreover, some allosteric drugs exert their effects only when the natural ligand is bound to the target protein, thus preserving the spatial and temporal activity of the natural ligand [ 112 ].…”