Automated design of ligands to polypharmacological profiles

Article

关键词: DE-NOVO DESIGN;    DRUG-DISCOVERY;    SMALL-MOLECULE;    IDENTIFICATION;    OPTIMIZATION;    PHARMACOLOGY;    ANTAGONISTS;    INHIBITORS;    PREDICTION;    PROGRAM;   

DOI  :  10.1038/nature11691

来源: SCIE

【 摘 要 】

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.

【 授权许可】

Free