title: Conformational adaptation in drug-target interactions and residence time.
abstract: Although drug-target interactions are commonly illustrated in terms of structurally static binding and dissociation events, such descriptions are inadequate to explain the impact of conformational dynamics on these processes. For high-affinity interactions, both the association and dissociation of drug molecules to and from their targets are often controlled by conformational changes of the target. Conformational adaptation can greatly influence the residence time of a drug on its target (i.e., the lifetime of the binary drug-target complex); long residence time can lead to sustained pharmacology and may also mitigate off-target toxicity. In this perspective, the kinetics of drug-target association and dissociation reactions are explored, with particular emphasis on the impact of conformational adaptation on drug-target residence time.
authors: Epizyme, Inc., 325 Vassar Street, Cambridge, MA 02139, USA. rcopeland@epizyme.com
authors: Robert A
authors: RA
authors: Copeland
mesh_terms: D003198:Computer Simulation; D006207:Half-Life; D007700:Kinetics; D008968:Molecular Conformation; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations; D011506:Proteins