Structural Insights into σ1 Receptor Interactions with Opioid Ligands by Molecular Dynamics Simulations

Abstract

Despite considerable advances over the past years in understanding the mechanisms of action and the role of the σ1 receptor, several questions regarding this receptor remain unanswered. This receptor has been identified as a useful target for the treatment of a diverse range of diseases, from various central nervous system disorders to cancer. The recently solved issue of the crystal structure of the σ1 receptor has made elucidating the structure–activity relationship feasible. The interaction of seven representative opioid ligands with the crystal structure of the σ1 receptor (PDB ID: 5HK1) was simulated for the first time using molecular dynamics (MD). Analysis of the MD trajectories has provided the receptor–ligand interaction fingerprints, combining information on the crucial receptor residues and frequency of the residue–ligand contacts. The contact frequencies and the contact maps suggest that for all studied ligands, the hydrophilic (hydrogen bonding) interactions with Glu172 are an important factor for the ligands’ affinities toward the σ1 receptor. However, the hydrophobic interactions with Tyr120, Val162, Leu105, and Ile124 also significantly contribute to the ligand–receptor interplay and, in particular, differentiate the action of the agonistic morphine from the antagonistic haloperidol.

Application of Molecular Dynamics in Coating Ag-Conjugated Nanoparticles with Potential Therapeutic Applications

“…The atomic motion and behavior of the compounds and their interactions with each other were studied by watching simulations' trajectories [43][44][45][46]. Our analyses showed that each of the active compounds in question was instantaneously attached to the NP (Fig.…”

Affinity of fentanyl and its derivatives for the σ1-receptor

“…cocaine and methamphetamine) which are shown to interact with the σ 1 R. 14 This raises questions as to the possible involvement of the receptor in the pharmacological action or side-effects of these drugs. 4,5,16 On the other hand, this fact can also pave the way for interesting repurposing programmes. Novel σ 1 R ligands could be developed by structural optimization of known drugs (with some σ 1 R binding) aimed at increasing the σ 1 R affinity while decreasing the affinity for the original major target.…”