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 stable configurations of the two drugs inside the receptor by simulating their escape routes by metadynamics, an algorithm that allows the simulation of events that are otherwise out of range for standard molecular dynamics simulations. Our results point out that the action of the compound is related to the spatial distribution of the affinity sites it visits during its permanency. Desmetilclozapine has a larger distribution of residues, which is interacting with, than clozapine. However, large conformational changes of the receptor were not observed in the presence of both compounds. Thus, a more dynamical picture of ligand-receptor affinity is proposed on the basis of the results obtained, involving the competition among different stable states as well as the interaction with the solvents. Such information might be useful to provide hints and insights that can be exploited in more structure-and-dynamics-oriented drug design.
Pathways to exit a receptor: a dynamical view of agonists - delta-opioids interaction
CECCARELLI, MATTEO;RUGGERONE, PAOLO
2011-01-01
Abstract
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 stable configurations of the two drugs inside the receptor by simulating their escape routes by metadynamics, an algorithm that allows the simulation of events that are otherwise out of range for standard molecular dynamics simulations. Our results point out that the action of the compound is related to the spatial distribution of the affinity sites it visits during its permanency. Desmetilclozapine has a larger distribution of residues, which is interacting with, than clozapine. However, large conformational changes of the receptor were not observed in the presence of both compounds. Thus, a more dynamical picture of ligand-receptor affinity is proposed on the basis of the results obtained, involving the competition among different stable states as well as the interaction with the solvents. Such information might be useful to provide hints and insights that can be exploited in more structure-and-dynamics-oriented drug design.
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