We have studied a human delta-opioid receptor interacting with two agonists, Clozapine and Desmethylclozapine. Delta-opioid receptors belong to the family of G protein-coupled receptors, that transduce an intracellular biological signal upon activation via interaction with a ligand in the transmembrane domain. Although Clozapine and Desmethylclozapine only differ by a methyl group, experimental data have evidenced a more efficient action of Desmethylclozapine in the treatment of refractory schizophrenia. A molecular analysis may help to clarify issues related this difference. Molecular Dynamics simulations help to elucidate the microscopic mechanism of the interactions between the ligand and the receptor identifying features barely seen in experiments. However, as in our case, the time scale of the processes of interest is often too long to be approached by standard MD techniques. Thus, for our study we have used a recent technique, the metadynamics, that accelerates MD runs extending simulation times. Our results pointed out different routes of the drugs inside the receptor: Clozapine touches a larger number of competing minima far from the putative receptor active zone than Desmethylclozapine. This latter spends most of its time inside the receptor close to the residues of the active zone, inducing noticeable structural modifications. Additionally, the simulation of the entrance has provided evidence of a stronger interaction with the receptor of Desmethylclozapine than Clozapine, resulting in a more frequent entrance of the former. Clozapine exhibits a preferential interaction with the membrane because of its enhanced hydrophobicity. The free energy surfaces extracted from the simulations have been used for kinetic Monte Carlo simulations to obtain reliable residence times of the drugs inside the receptor. The whole results helps to understand how microscopic details can remarkably affect efficiency and activity of compounds, supporting the idea of a bottom-up strategy in the drug design.
A Molecular Approach to Ligand-Receptor Interaction
CECCARELLI, MATTEO;RUGGERONE, PAOLO
2009-01-01
Abstract
We have studied a human delta-opioid receptor interacting with two agonists, Clozapine and Desmethylclozapine. Delta-opioid receptors belong to the family of G protein-coupled receptors, that transduce an intracellular biological signal upon activation via interaction with a ligand in the transmembrane domain. Although Clozapine and Desmethylclozapine only differ by a methyl group, experimental data have evidenced a more efficient action of Desmethylclozapine in the treatment of refractory schizophrenia. A molecular analysis may help to clarify issues related this difference. Molecular Dynamics simulations help to elucidate the microscopic mechanism of the interactions between the ligand and the receptor identifying features barely seen in experiments. However, as in our case, the time scale of the processes of interest is often too long to be approached by standard MD techniques. Thus, for our study we have used a recent technique, the metadynamics, that accelerates MD runs extending simulation times. Our results pointed out different routes of the drugs inside the receptor: Clozapine touches a larger number of competing minima far from the putative receptor active zone than Desmethylclozapine. This latter spends most of its time inside the receptor close to the residues of the active zone, inducing noticeable structural modifications. Additionally, the simulation of the entrance has provided evidence of a stronger interaction with the receptor of Desmethylclozapine than Clozapine, resulting in a more frequent entrance of the former. Clozapine exhibits a preferential interaction with the membrane because of its enhanced hydrophobicity. The free energy surfaces extracted from the simulations have been used for kinetic Monte Carlo simulations to obtain reliable residence times of the drugs inside the receptor. The whole results helps to understand how microscopic details can remarkably affect efficiency and activity of compounds, supporting the idea of a bottom-up strategy in the drug design.
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