Drug–target residence time: critical information for lead optimization

Failure due to poor in vivo efficacy is a primary contributor to attrition during the development of new chemotherapeutics. Lead optimization programs that in their quest for efficacy focus solely on improving the affinity of drug–target binding are flawed, since this approach ignores the fluctuations in drug concentration that occur in vivo. Instead the lifetime of the drug–target complex must also be considered, since drugs only act when they are bound to their targets. Consequently, to improve the correlation between the in vitro and in vivo activity of drugs, measurements of drug–target residence time must be incorporated into the drug discovery process.