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.
Pubmed ID: 23235874 RIS Download
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Collection of bioactive drug-like small molecules that contains 2D structures, calculated properties and abstracted bioactivities. Used for drug discovery and chemical biology research. Clinical progress of new compounds is continuously integrated into the database.
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View all literature mentionsSoftware used to automate the process of accessing, analyzing and reporting scientific data. This software can be used by a person with little or no software development experience can create scientific protocols that can be executed through a variety of interfaces including: BIOVIA Web Port, other BIOVIA solutions such as BIOVIA Electronic Lab Notebook, Isentris, Chemical Registration and third-party applications such as Microsoft SharePoint. The protocols aggregate and provide immediate access to volumes of research data, they automate the scientific analysis of data and allow researchers to explore, visualize and report results.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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