Determination of structural factors affecting binding to mu, kappa and delta opioid receptors

Addiction is a complex behavioral phenomenon in which naturally occurring or synthetic chemicals modulate the response of the reward system through their binding to a variety of neuroreceptors, resulting in compulsive substance-seeking and use despite harmful consequences to the individual. Among these, the opioid receptor (OR) family and more specifically, the mu-opioid receptor (MOR) subtype plays a critical role in the addiction to powerful prescription and illicit drugs such as hydrocodone, oxycodone, fentanyl, cocaine, and methamphetamine (Contet et al. in Curr Opin Neurobiol 14(3):370-378, 2004). Conversely, agonists binding to kappa (KOR) and antagonists binding to delta opioid receptors (DOR) have been reported to induce negative reinforcing effects. As more than 700 new psychoactive substances were illegally sold between 2009 and 2016 (DEA-DCT-DIR-032-18), most of them lacking basic toxicological and pharmacological profiles, molecular modeling approaches that could quickly and reliably fill the gaps in our knowledge would be highly desirable tools for determining the effects of these synthetics. Here, we report accurate 3D-spectrometric data-activity relationship classification models for large and diverse datasets of MOR, KOR and DOR binders with areas under the receiver operating characteristic curve for the "blind" prediction sets exceeding 0.88. Structural features associated with (selective) binding to MOR, KOR and/or DOR were identified. These models could assist regulatory agencies in evaluating the health risks associated with the use of unprofiled substances as well as to help the pharmaceutical industry in its search for new drugs to combat addiction.