期刊
NATURE
卷 492, 期 7428, 页码 215-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11691
关键词
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资金
- SULSA [HR07019]
- BBSRC Doctoral Training Programme
- BBSRC Pathfinder [BB/FOF/PF/15/09]
- BBSRC [BB/J010510/1]
- University of Dundee's Pump Priming Fund for Translational Medical Research
- National Institutes of Health (NIH) [MH082441]
- Wellcome Trust [WT 083481]
- North Carolina Biotechnology Center
- Michael Hooker Chair of Pharmacology
- BBSRC [BB/J010510/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J010510/1] Funding Source: researchfish
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.
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