title: Automated design of ligands to polypharmacological profiles.
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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Besnard
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.forename: Vincent
authors.initials: V
authors.lastname: Setola
authors.forename: Keren
authors.initials: K
authors.lastname: Abecassis
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Maria F
authors.initials: MF
authors.lastname: Sassano
authors.forename: Antony I
authors.initials: AI
authors.lastname: Shin
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Webster
authors.forename: Frederick R C
authors.initials: FR
authors.lastname: Simeons
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Constam
authors.forename: G Richard
authors.initials: GR
authors.lastname: Bickerton
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hopkins
mesh_terms: D000818:Animals; D001331:Automation; D016503:Drug Delivery Systems; D015195:Drug Design; D005260:Female; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008962:Models, Theoretical; D000069437:Pharmacological Phenomena; D015203:Reproducibility of Results
chemical_list: D008024:Ligands