Molecular dynamics study of M-Trifluoromethyl diphenyl diselenide binding to the μ-opioid receptor: A computational...

Chronic pain is a maladaptive state where pain signals persist beyond the expected resolution of injury or illness. Morphine and related compounds, acting as µ-opioid receptor (µOR) agonists, are effective analgesics for managing this condition. However, chronic morphine administration can disrupt µOR trafficking and activate β-arrestin-mediated pathways, leading to opioid tolerance. The role of µOR in mood disorders is less well-defined. The organoselenium compound m-trifluoromethyl diphenyl diselenide (TFDD) has shown promising antinociceptive and antidepressant-like effects in experimental models and attenuated morphine withdrawal symptoms in mice.¹ However, the molecular mechanisms governing TFDD's interaction with the µOR at the atomic level remain unexplored through theoretical methodologies. To bridge this knowledge gap, the current research sought to characterize the pharmacological profile of TFDD using an integrated computational approach that included quantum chemical calculations, molecular dynamics simulations, and thermodynamic analysis. The simulations revealed the formation of persistent halogen bonds between TFDD's trichlorobenzene moiety and specific residues within the µOR binding pocket, namely Gln124^2.60 and Glu299^5.58 with bond distances of 2.83 and 3.73 Å respectively. These interactions, spanning transmembrane helices 2 through 5 (TM2-TM5), contribute to the stabilization of TFDD within the receptor's binding site. Notably, key microswitch residues, such as Asp147^3.32, Met151^3.36, and Trp293^6.48, which are critical for maintaining the µOR active conformation and modulating β-arrestin signaling, were observed to interact with TFDD. These conformational dynamics subsequently influence the G protein-biased activation of the µOR. To examine the conformational space of the µOR bound to TFDD and the morphinan agonist BU72, principal component analysis was used to determine the leading modes of motion. Subsequently, free energy landscapes were constructed to identify energetically favorable conformational states and the transitions between them, providing insights into the thermodynamic behavior of the µOR-ligand bound complexes. Furthermore, dynamic cross-correlation matrix analysis was performed to evaluate differences in the correlated motions of µOR residues upon binding of BU72 and TFDD. Alchemical free energy calculations, utilizing thermodynamic integration across various λ states, were employed to quantitatively estimate the binding affinities of both ligands TFDD and BU72. The calculated total binding free energy values were -42.54 ± 1.92 kJ/mol for TFDD and -39.76 ± 0.74 kJ/mol for BU72. This computational study elucidates the molecular basis of TFDD's interaction with µOR, integrating experimental data with atomic-level modeling. This enhances our understanding of TFDD's potential to reduce morphine tolerance, improve pain relief, and minimize side effects, ultimately informing the development of better opioid-based pain management strategies.