Molecular determinants of drug-receptor binding kinetics

Drug Discov Today. 2013 Jul;18(13-14):667-73. doi: 10.1016/j.drudis.2013.02.007. Epub 2013 Feb 27.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Binding Sites
  • Drug Design*
  • Humans
  • Kinetics
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding
  • Protein Conformation
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Structure-Activity Relationship


  • Ligands
  • Pharmaceutical Preparations
  • Receptors, Cell Surface
  • Receptors, Cytoplasmic and Nuclear