Pharmacological plasticity-How do you hit a moving target?

Pharmacol Res Perspect. 2019 Nov 21;7(6):e00532. doi: 10.1002/prp2.532. eCollection 2019 Dec.

Abstract

Paul Ehrlich's concept of the magic bullet, by which a single drug induces pharmacological effects by interacting with a single receptor has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic variability, cellular plasticity, chronobiological rhythms, time, age and disease resolution, sex, drug metabolism, and distribution. We emphasize four existing approaches that can be taken, either singly or in combination, to try to minimize effects of pharmacological plasticity. These are firstly, to enhance specificity using target conditions close to those in diseases, secondly, by simultaneously or thirdly, sequentially aiming at multiple targets, and fourthly, in synchronization with concurrent dietary, psychological, training, and biorhythm-synchronizing procedures to optimize drug therapy.

Keywords: Drug therapy; chronobiology; drug metabolism and distribution; drug targets; target variability.

Publication types

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

MeSH terms

  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Humans
  • Ligands
  • Molecular Targeted Therapy / methods*
  • Pharmacology, Clinical / methods*

Substances

  • Ligands