Though many drugs achieve efficacy via activity on multiple targets, the discovery of such drugs is typically serendipitous and their mechanism of action is usually understood only in retrospect, if at all. This is especially true for psychiatric drugs, which simultaneously target a number of aminergic G protein-coupled receptors (GPCRs). With the recent influx of receptor structural information and enumeration of large virtual libraries, we wondered if structure-based methods could find molecules with a predefined polypharmacology. Here, we explore the ability of molecular docking, at both homology models and crystal structures, to find ligands with activity at two psychiatrically relevant GPCR targets and with selectivity against closely related GPCR antitargets. In a second campaign, we employ a different docking pipeline to discriminate between members of the opioid family. Whereas docking can find molecules with the desired pharmacologic profiles, often with a high success rate, the ability to select against related anti-targets is modest at best. Strategies to minimize false positives and false negatives, traditional liabilities of structure-based methods, are evaluated, and the roles of receptor flexibility and intrinsic receptor promiscuity in designed polypharmacology and specificity are considered.

Challenges and opportunities in structure-based discovery for GPCR targets and antitargets

255th National Meeting (2018)

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