title: A structural insight into the negative effects of opioids in analgesia by modulating the TLR4 signaling: An in silico approach.
abstract: Opioids are considered the gold standard therapy for pain. However, TLR-dependent negative effects in analgesia have highlighted the complexities in the pharmacodynamics of opioids. While successive studies have reported that morphine and Morphine-3-glucuronide (M3G) activate the TLR4 pathway, the structural details of this mechanism are lacking. Here, we have utilized various computational tools to reveal the structural dynamics of the opioid-bound TLR4/MD2 complex, and have proposed a potential TLR4 activation mechanism. Our results support previous findings, and include the novel insight that the stable binding of morphine and naloxone, but not M3G, in the MD2 cavity, is TLR4 dependent. Morphine interacts with MD2 near its Phe126 loop to induce the active conformation (MD2C); however, this binding is likely reversible, and the complex gains stability upon interaction with TLR4. M3G also induces the MD2Cstate, with both the Phe126 loop and the H1 loop being involved in MD2-M3G complex stability. Remarkably, naloxone, which requires TLR4 interaction for complex stability, switches the conformation of the gating loop to the inactive state (MD2°). Cumulatively, our findings suggest that ligand binding and receptor clustering occur successively in opioid-induced TLR4 signaling, and that MD2 plasticity and pocket hydrophobicity are crucial for the recognition and accommodation of ligands.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Masaud
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Muhammad Ayaz
authors.initials: MA
authors.lastname: Anwar
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Dhanusha
authors.initials: D
authors.lastname: Yesudhas
authors.affiliation: Department of Life Sciences, Central University of Tamil Nadu, Neelakudi, Thiruvarur, Tamil Nadu, India.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Krishnan
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D006860:Hydrogen Bonding; D008024:Ligands; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009020:Morphine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009022:Morphine Derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009270:Naloxone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D025341:Principal Component Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects*; D013816:Thermodynamics; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; D009022:Morphine Derivatives; D051197:Toll-Like Receptor 4; D009270:Naloxone; D009020:Morphine; C018108:morphine-3-glucuronide