title: The design of covalent allosteric drugs.
abstract: A key issue in drug discovery is how to reduce drug dosage and increase specificity while retaining or increasing efficacy, as high dosage is often linked to toxicity. There are two types of drugs on the market: orthosteric and allosteric. Orthosteric drugs can be noncovalent or covalent. The latter are advantageous because they may be prescribed in lower doses, but their potential off-target toxicity is a primary concern. The chief advantages of allosteric drugs are their higher specificity and their consequently lower chance of toxic side effects. Covalent allosteric drugs combine the pharmacological merits of covalent drugs with the additional benefit of the higher specificity of allosteric drugs. In a recent promising step in therapeutic drug development, allosteric, disulfide-tethered fragments successfully modulated the activity of a protein kinase and K-Ras.
authors.affiliation: Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland 21702; email: NussinoR@helix.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: Chung-Jung
authors.initials: CJ
authors.lastname: Tsai
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D017076:Computer-Aided Design; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000517:prevention & control; D020536:Enzyme Activators / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D020536:Enzyme Activators; D004791:Enzyme Inhibitors
keywords: agonist; allosteric drug discovery; allosteric modulator; antagonist; pharmacology; toxicity