Deciphering the molecular basis of the kappa opioid receptor selectivity: A Molecular Dynamics study
| Autor: | Ahmad Abdelwaly, Khaled M. Darwish, Mohamed A. Helal, Amal A.M. Eissa, Amr H. Saleh, Amar G. Chittiboyina |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.drug_class
Narcotic Antagonists Molecular Dynamics Simulation Pharmacology Ligands 01 natural sciences κ-opioid receptor 03 medical and health sciences chemistry.chemical_compound Opioid receptor 0103 physical sciences Materials Chemistry Alvimopan medicine Physical and Theoretical Chemistry Spectroscopy 030304 developmental biology 0303 health sciences 010304 chemical physics Receptors Opioid kappa Antagonist JDTic Computer Graphics and Computer-Aided Design chemistry Receptors Opioid Opiate μ-opioid receptor Selectivity medicine.drug |
| Zdroj: | Journal of Molecular Graphics and Modelling. 106:107940 |
| ISSN: | 1093-3263 |
| DOI: | 10.1016/j.jmgm.2021.107940 |
| Popis: | Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction, as well as depression and other CNS disorders. Over the years, the development of KOP-selective antagonists yielded very few successful compounds. Recently, N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have emerged as a novel class of pure opioid receptor antagonists, including the marketed Mu opioid receptor (MOP) peripheral antagonist Alvimopan and the potent KOP antagonist JDTic. However, the selectivity determinants of this class of compounds towards the opioid receptor subtypes are still vague and understudied. In this work, we have performed Molecular Dynamics (MD) simulation to gain insights into the differential binding of this class of compounds into KOP, as exemplified by Alvimopan and JDTic. Our study indicated that the selectivity largely depends on ligands interaction with the selectivity pocket formed by Val108, Thr111, and Val118, supported by two additional polar and hydrophobic contacts with Asp138 and Trp287, respectively. Our results also demonstrate, for the first time, that non-morphinan ligands can still adopt the "message-address model" for KOP efficacy and selectivity by binding to Glu297. |
| Databáze: | OpenAIRE |
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