The different ways through which specificity works in orthosteric and allosteric drugs.
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.
NCI-Frederick Bldg, Frederick, MD 21702, USA. ruthnu@helix.nih.gov
Ruth
R
Nussinov
Chung-Jung
CJ
Tsai
D000494:Allosteric Regulation; D000495:Allosteric Site; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
D004364:Pharmaceutical Preparations; D011506:Proteins