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