Promiscuity of in Vitro Secondary Pharmacology Assays and Implications for Lead Optimization Strategies

• Published in: Journal of medicinal chemistry Vol. 63; no. 12; pp. 6251 - 6275
• Main Authors: Brown, Dean G, Smith, Graham F, Wobst, Heike J
• Format: Journal Article
• Language: English
• Published: American Chemical Society 25.06.2020
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01625

We conducted an analysis on screening data generated from 1445 compounds against a panel of 130 enzymes, ion channels, and receptors to assess secondary pharmacological risks. Hit rates of these targets as well as physicochemical properties for those hits were evaluated. A majority of targets yielded hits with higher clogP, molecular weight, and more basic character than inactive compounds. Although most targets favored lipophilic hits, the average clogP of hits at a given target did not correlate with its hit rate. Furthermore, a matched pair analysis was completed to determine structural changes that impacted off-target activities. A correlation of binding assays used in this analysis illustrated that some pharmacologically related binding assays are highly correlative and may be substituted for a smaller set of surrogate assays.