title: Molecular determinants of drug-receptor binding kinetics.
abstract: It is increasingly appreciated that the rates at which drugs associate with and dissociate from receptors--the binding kinetics--directly impact drug efficacy and safety. The molecular determinants of drug-receptor binding kinetics remain poorly understood, however, especially when compared with the well-known factors that affect binding affinity. The rational modulation of kinetics during lead optimization thus remains challenging. We review some of the key factors thought to control drug-receptor binding kinetics at the molecular level--molecular size, conformational fluctuations, electrostatic interactions and hydrophobic effects--and discuss several possible approaches for the rational design of drugs with desired binding kinetics.
authors: DE Shaw Research, New York, NY 10036, USA. Albert.Pan@DEShawResearch.com
authors: Albert C
authors: AC
authors: Pan
authors: David W
authors: DW
authors: Borhani
authors: Ron O
authors: RO
authors: Dror
authors: David E
authors: DE
authors: Shaw
mesh_terms: D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear