Automated design of ligands to polypharmacological profiles.

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Besnard, J; Ruda, GF; Setola, V; Abecassis, K; Rodriguiz, RM; Huang, X-P; Norval, S; Sassano, MF; Shin, AI; Webster, LA; Simeons, FRC; Stojanovski, L; Prat, A; Seidah, NG; Constam, DB; Bickerton, GR; Read, KD; Wetsel, WC; Gilbert, IH; Roth, BL; Hopkins, AL

Published Date

  • December 13, 2012

Published In

Volume / Issue

  • 492 / 7428

Start / End Page

  • 215 - 220

PubMed ID

  • 23235874

Pubmed Central ID

  • 23235874

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/nature11691


  • eng

Conference Location

  • England