The different ways through which specificity works in orthosteric and allosteric drugs

Abstract

Currently, there are two types of drugs on the market: orthosteric, which bind at the active site; and allosteric, which bind elsewhere on the protein surface, and allosterically change the conformation of the protein binding site. In this perspective we argue that the different mechanisms through which the two drug types affect protein activity and their potential pitfalls call for different considerations in drug design. The key problem facing orthosteric drugs is side effects which can occur by drug binding to homologous proteins sharing a similar binding site. Hence, orthosteric drugs should have very high affinity to the target; this would allow a low dosage to selectively achieve the goal of target-only binding. By contrast, allosteric drugs work by shifting the free energy landscape. Their binding to the protein surface perturbs the protein surface atoms, and the perturbation propagates like waves, finally reaching the binding site. Effective drugs should have atoms in good contact with the 'right' protein atoms; that is, the contacts should elicit propagation waves optimally reaching the protein binding site target. While affinity is important, the design should consider the protein conformational ensemble and the preferred propagation states. We provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development.

Fig. (1).

This simplified diagram illustrates the fundamental mechanisms of how allosteric drugs and orthosteric drugs work. A functional protein (blue) is represented by two binding sites. An allosteric drug (pink) binds to the allosteric site and an orthosteric drug (green) binds to the orthosteric site. The mechanism of inhibition depicted here illustrates that a drug binding event can prevent either an agonist or substrate (orange) from binding to the orthosteric site. To achieve inhibition, the orthosteric drug has to compete with an agonist or substrate for binding at the same site. On the other hand, the allosteric drug achieves inhibition via propagation of the strain energy (depicted by the red ‘bump’ and the change in the ellipsoid contacts) which is created at the binding interface, to the orthosteric site. This causes a conformational change at the orthosteric site and alters the binding affinity.

Fig. (2).

This simplified diagram illustrates how allosteric drugs and orthosteric drugs achieve specificity to avoid side effects. As in Fig. (1), the functional homolog (blue) is also represented by two binding sites with the allosteric drug (pink) binding to an allosteric site and the orthosteric drug (green) to the orthosteric site. Because binding sites in homologous proteins are typically more similar than other locations on the protein surfaces, in the drawing the shapes of the orthosteric sites are more similar than those of the allosteric sites. Thus, to achieve specificity for a specific binding site, orthosteric drugs generally need to undergo fine-tuning. This is illustrated by dark green shape complementarity between the homologous sites and their respective orthosteric drugs. By contrast, the allosteric drug can achieve specificity more easily, because the allosteric sites are more different among the protein homologs.