Retrospective Analysis of Chemical Structure-Based in silico Prediction of Primary Drug Target and Off-Targets

In early phases of the drug discovery process, evaluating the off-target pharmacology of a candidate drug is important when considering potential safety risks. Such off-target liabilities are most commonly evaluated using panels of in vitro pharmacology assays with strong association to well-defined toxicological events. In addition to in vitro panels, preliminary in silico evaluation is emerging as a valuable approach to support identification of potential off-target hits, even prior to synthesis of chemical material. To ascertain the utility of in silico target profiling, the predictive performance of a proprietary in silico predictive tool was evaluated against an in-house data set of 94 compounds with associated in vitro panel data, including binding inhibition and functional agonism/antagonism. Of the compounds tested, the primary target was predicted with 35% sensitivity. However, the sensitivity to predict the primary target decreased to 16% for a subset of compounds not reported within the Chemical Abstracts Service registry. For the known off-target hits for all tested compounds, the value of sensitivity was 16% for binding assays and 23% for functional assays. To better understand the applicability of the in silico off-target prediction, we performed in vitro binding assays, to evaluate five additional off-targets that were predicted by in silico but not covered by our standard off-target binding or functional panels. Although no new off-target hit was identified through this campaign, as technologies evolve, the in silico predictions could provide valuable insights to identify potential off-targets and mechanistic insights on target organ toxicities caused by compounds in in vivo studies.