On-rate based optimization of structure-kinetic relationship--surfing the kinetic map

Drug Discov Today Technol. 2015 Oct;17:9-15. doi: 10.1016/j.ddtec.2015.08.003. Epub 2015 Sep 18.


In the lead discovery process residence time has become an important parameter for the identification and characterization of the most efficacious compounds in vivo. To enable the success of compound optimization by medicinal chemistry toward a desired residence time the understanding of structure-kinetic relationship (SKR) is essential. This article reviews various approaches to monitor SKR and suggests using the on-rate as the key monitoring parameter. The literature is reviewed and examples of compound series with low variability as well as with significant changes in on-rates are highlighted. Furthermore, findings of kinetic on-rate changes are presented and potential underlying rationales are discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Drug Discovery*
  • Kinetics
  • Pharmaceutical Preparations / chemistry
  • Pharmaceutical Preparations / metabolism*
  • Protein Binding
  • Proteins / metabolism*
  • Structure-Activity Relationship


  • Pharmaceutical Preparations
  • Proteins