In silico exploration of antinociceptive activity of 1,4-benzodiazepines: Molecular docking on α1 A-adrenoceptor, and phosphodiesterase 4

Abstract

Recently, scientists have established that several benzodiazepines were found to enhance the activation of a cAMP response element pathway by α1A-adrenergic receptors, but this effect was attributed to off-target inhibition of phosphodiesterases 4. The study explores the pain-relief potential of 1,4-benzodiazepines using in silico methods, focusing on their interaction with α1A-adrenoceptors (α1-AR) and phosphodiesterase 4 (PDE4). AutoDock Vina-1.2.5 and Glide (Schrödinger Suite) (2023-2) were used to calculate the binding affinities and determine the features of their interactions by the molecular docking method; PlayMolecule software was used to perform molecular dynamics. Propoxazepam exhibits moderate free binding energy for α1A-adrenoceptors, as indicated by its average molecular mechanics/generalized Born surface area (MMGBSA) and Glide Score values. Compared to propoxazepam, 3-hydroxypropoxazepam has enhanced predicted affinity values for the alpha 1A adrenergic receptor, primarily due to the hydroxyl group, which facilitates the formation of additional hydrogen bonds. Propoxazepam, along with its metabolite 3-hydroxypropoxazepam, demonstrates promising interactions with PDE4A, characterized by notably low predicted free binding energy MMGBSA and strong binding affinity computed via AutoDock Vina. Among other ligands, propoxazepam demonstrates the lowest MMGBSA value with PDE4A (phosphodiesterase 4A). The best predicted binding scores of interaction with phosphodiesterase 4 is observed for propoxazepam with PDE4B (phosphodiesterase 4B) -10.3 kcal/mol, according to AutoDock Vina. Propoxazepam and its derivative 3-hydroxypropoxazepam interact with the active sites of PDE4B and PDE4D (phosphodiesterase 4 B) via a “hydrophobic clamp”, a typical binding mode for PDE inhibitors, which relies on crucial hydrophobic interactions. Binding of propoxazepam and its metabolite 3-hydroxypropoxazepa to PDE4B reduces the fluctuations of M-pocket residues and supports the conclusion that ligand binding stabilizes the protein structure of PDE4B. The MMGBSA method predicts that propoxazepam and 3-hydroxypropoxazepam have the most favourable predicted binding energies with PDE4D (2FMO). Since 1,4-benzodiazepines bind to phosphodiesterase 4 similarly to its inhibitors, this may support the hypothesis that benzodiazepines may affect α1-AR by inhibiting PDE4. The study of the binding mechanisms of 1,4-benzodiazepines with phosphodiesterase 4 and alpha-1A adrenoceptors helps to expand the understanding of the analgesic and anti-inflammatory effect of benzodiazepines associated with these proteins, which can be taken into account in the development of new analgesic and anti-inflammatory agents.