Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets.

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ID: 52883
2018
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Abstract
To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D and serotonin 5-HT receptors were targeted, seeking selectivity against the histamine H receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D/5-HT ligand with 21-fold selectivity versus the H receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.
Reference Key
weiss2018selectivityjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Weiss, Dahlia R;Karpiak, Joel;Huang, Xi-Ping;Sassano, Maria F;Lyu, Jiankun;Roth, Bryan L;Shoichet, Brian K;
Journal Journal of medicinal chemistry
Year 2018
DOI
10.1021/acs.jmedchem.8b00718
URL
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