Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 15, Pages 6830-6845Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00718
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Funding
- U.S. National Institutes of Health [R35 GM122481, F32 GM093580]
- NIMH Psychoactive Drug Screening Program (NIMH PDSP)
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To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D-2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H-1 receptor. In a second campaign, x-opioid receptor ligands were sought with selectivity versus the mu-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-2/5-HT2A ligand with 21-fold selectivity versus the H-1 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.
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