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Exploring binding properties of agonists interacting with a ?-opioid receptor.

ABSTRACT: Ligand-receptor interactions are at the basis of the mediation of our physiological responses to a large variety of ligands, such as hormones, neurotransmitters and environmental stimulants, and their tuning represents the goal of a large variety of therapies. Several molecular details of these interactions are still largely unknown. In an effort to shed some light on this important issue, we performed a computational study on the interaction of two related compounds differing by a single methyl group (clozapine and desmethylclozapine) with a [Formula: see text]-opioid receptor. According to experiments, desmethylclozapine is more active than clozapine, 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 molecular dynamics simulations. Our results point out that the action of the compounds might be related to the spatial and temporal distribution of the affinity sites they visit during their permanency. Moreover, no particularly pronounced structural perturbations of the receptor were detected during the simulations, reinforcing the idea of a strong dynamical character of the interaction process, with an important role played by the solvent in addition.

SUBMITTER: Collu F

PROVIDER: S-EPMC3530460 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Exploring binding properties of agonists interacting with a δ-opioid receptor.

Collu Francesca F Ceccarelli Matteo M Ruggerone Paolo P

PloS one 20121226 12

Ligand-receptor interactions are at the basis of the mediation of our physiological responses to a large variety of ligands, such as hormones, neurotransmitters and environmental stimulants, and their tuning represents the goal of a large variety of therapies. Several molecular details of these interactions are still largely unknown. In an effort to shed some light on this important issue, we performed a computational study on the interaction of two related compounds differing by a single methyl ...[more]

PMID: 23300729

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Project description:Since estrogen-related receptor alpha (ERRα), one of three estrogen-related receptors, displays constitutively active transcriptional activities and important implications in both physiological and pathological processes of breast cancers, ERRα was recently recognized as a new target to fight breast cancers, and regulating the activity of ERRα with inverse agonists has thus become a promising new therapeutic strategy. A few inverse agonists cyclohexylmethyl-(1-p-tolyl-1H-indol-3-ylmethyl)-amine (compound 1), thiadiazoacrylamide (XCT790), and 1-(2,5-diethoxy-benzyl)-3-phenyl-area analogues (compounds 2 and 3) were reported to be capable of targeting ERRα. However, the detailed mechanism by which the inverse agonists deactivate ERRα remains unclear, especially in the aspects of quantitative binding and hot spot residues. Therefore, to gain insights into the interaction modes between inverse agonists and ERRα ligand binding domain, all-atom molecular dynamics (MD) simulations were firstly carried out for the complexes of inverse agonists and ERRα. The binding free energies were then calculated with MM-PBSA method to quantitatively discuss the binding of the inverse agonists with ERRα. The binding affinities were finally decomposed to per-residue contributions to identify the hot spot residues as well as assess their role in the binding mechanism. MD simulations show that the inverse agonists stretch downwards into the ERRα ligand binding pocket (LBP) formed by H3 and H11 helices, and upon the binding H12 adopts a well-defined position in the coactivator groove, where PGC-1α binds to ERRα. Binding energy analysis indicates that compound 3 and XCT790 bind more tightly to ERRα than compounds 1 and 2, and the energy difference mainly results from the contribution of van der Waals interaction. Both binding mode analysis and affinity decomposition per-residue indicate that compound 1, XCT790, and compound 3 have similar binding spectra to ERRα, primarily interacting with the residues of H3, H5, H6/H7 loop, and H11 helix, while compound 2 lacks a significant interaction with the H5 region. The hot spot residues significantly binding to the three inverse agonists in common include Leu324, Phe328, Phe382, Leu398, Phe495, and Leu500. It is essential for an effective inverse agonist to strongly bind with the aromatic ring cluster consisting of Phe328(H3), Phe495(H11), and Phe382(H5/H6 loop) as well as Leu500.

Dataset Information

Exploring binding properties of agonists interacting with a ?-opioid receptor.

Publications

Exploring binding properties of agonists interacting with a δ-opioid receptor.

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