Automated Design of Ligands to Polypharmacological Profiles

Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.

Abstract

The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Automation
  • Drug Delivery Systems
  • Drug Design*
  • Female
  • Ligands*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Theoretical
  • Pharmacological Phenomena
  • Reproducibility of Results

Substances

  • Ligands