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Automated design of ligands to polypharmacological profiles.
Nature ; 492(7428): 215-20, 2012 Dec 13.
Article em En | MEDLINE | ID: mdl-23235874
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Desenho de Fármacos / Ligantes Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Desenho de Fármacos / Ligantes Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2012 Tipo de documento: Article