RESUMO
During the past five years, the three-dimensional structures of 14 different G-protein coupled receptors (GPCRs) have been resolved by X-ray crystallography. The most recently published structures, those of the opioid receptors (ORs), are remarkably important in pain modulation, drug addiction, and mood disorders. These structures, confirmed previously proposed key interactions conferring potency and antagonistic properties, including the well-known interaction with Asp138, conserved in all aminergic GPCRs. In addition, crystallization of the opioid receptors highlighted the potential function of the ECL2 and ICL2 loops. We have previously reported a set of potent and selective kappa opioid receptor peptide agonists, of which ff(D-nle)r-NH2 is among the most potent and selective ones. These peptides were identified from the deconvolution of a 6,250,000 tetrapeptide combinatorial library. A derivative of this set is currently the subject of a phase 2 clinical trial in the United States. In this work, we describe comparative molecular modeling studies of kappa-OR peptide agonists with the co-crystallized antagonist, JDTic, and also report structure-activity relationships of 23 tetrapeptides. The overall binding and contact interactions are sound and interactions known to favor selectivity and potency were observed. Additional modeling studies will reveal conformational changes that the kappa-OR undergoes upon binding to these peptide agonists.
Assuntos
Receptores Opioides kappa/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Ligantes , Modelos Moleculares , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Peptídeos Cíclicos/farmacologia , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacologia , Ligação Proteica , Conformação Proteica , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/antagonistas & inibidores , Receptores Opioides kappa/química , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologiaRESUMO
A molecular modeling study on 16 1-benzyl tetrahydroisoquinolines (BTHIQs) acting as dopaminergic ligands was carried out. By combining molecular dynamics simulations with ab initio and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of BTHIQs interacting with the human dopamine D2 receptor (D2 DR) is reported here, providing a clear picture of the binding interactions of BTHIQs from both structural and energetic viewpoints. Molecular aspects of the binding interactions between BTHIQs and the D2 DR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental pKi values was obtained, predicting the potential dopaminergic effect of non-synthesized BTHIQs.