Pathways to Exit a Receptor: Agonists and Delta-Oppioid Studied via Computer Simulations

The importance of delta-opioid receptors as target of a large number of drugs is well recognized, but the molecular details of interaction and action of the compounds are largely unknown. In an effort to shade some light on this important issue we performed an extensive computational study on the interaction of two compounds, clozapine and desmetilclozapine, with a delta-opioid receptor. According to experiments, the lacking of a single methyl group in desmetilclozapine with respect of clozapine makes the former more active than the latter, providing a system well suited for a comparative study. We investigated the escape route of the two drugs from the receptor using molecular dynamics simulations and metadynamics. Our results point out that prolonged interactions of the compounds with specific residues of the receptor do not correlate directly with their activity, having clozapine the longest interactions if compared with desmetilclozapine but being also less active. The action of the compound is related to the spatial distribution of the affinity sites it visits during its permanency. Additionally, the role of long-resident water molecules is discussed. Such information might be useful to provide hints and insights that can be exploited in more structure-and-dynamics-oriented drug design.