Department of Pharmaceutical Chemistry , University of California-San Francisco , San Francisco , California 94158-2550 , United States.
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine , University of North Carolina , Chapel Hill , North Carolina 27599 , United States.
J Med Chem. 2018 Aug 9;61(15):6830-6845. doi: 10.1021/acs.jmedchem.8b00718. Epub 2018 Jul 24.
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.
为了研究大型库对接发现具有针对靶标联合活性和针对抗靶标选择性的分子的能力，针对多巴胺 D 和血清素 5-HT 受体进行了研究，旨在针对组胺 H 受体寻求选择性。在第二次活动中，针对 κ-阿片受体配体进行了研究，以针对 μ-阿片受体寻求选择性。虽然针对靶标，命中率范围为 40%至 63%，但它们针对抗靶标也同样有效，尽管这些分子是根据它们假定不与非靶标结合而选择的。亲和力通常也与非靶标一样好或更好。尽管偶尔可以找到选择性分子，例如具有针对 H 受体 21 倍选择性的中纳摩尔 D/5-HT 配体，但这是例外。虽然在针对靶标的对接筛选中假阴性是可以接受的，但在针对抗靶标时是不可接受的；解决这个问题可能需要该领域的新策略。
