Allosteric modulation of laeviganoid-based clerodane diterpenes derivatives in muscarinic acetylcholine M1 receptor against tinnitus: a structure-based virtual screening approach

Abstract Background Chronic tinnitus is a complication that affects the central nervous system, specifically the auditory cortex, causing a phantom perception of sounds and noises without any external acoustic stimulus. It is more frequent in men than in women and can be caused by excessive exposure to auditory stimuli. The main modulator of auditory functions, particularly in terms of neuroplasticity in the auditory system, is the M1 muscarinic acetylcholine receptor (mAChR M1). In the literature, natural oxygenated heterocyclic compounds have been used to develop drugs that act on the central nervous system (CNS), including clerodane diterpenes. The aim of this study was to evaluate the modulatory action of a series of naturally occurring clerodane diterpenes against chronic tinnitus. Results The structure-based virtual screening revealed that Laeviganoid derivatives L1-8 share structural similarities with other oxygenated heterocyclic compounds that modulate mAChR M1. The prediction of pharmacokinetic properties highlighted the L4 derivative as a potential candidate for distribution in the CNS due to its high cell permeability (P app,A→B = 1.9 × 10 −5 cm/s) and metabolic stability. Molecular docking simulations indicate that the ligand interacts with the active site of mAChR M1 through hydrophobic interactions with residues Tyr106, Trp378, Tyr381 and Tyr404, with an affinity energy of approximately − 8.7 kcal/mol. Molecular dynamics simulations have shown that the L4/M1 complex is stable as a function of time (200 ns). Conclusion The in silico results suggest that the L4 can perform allosteric modulation of mAChR M1 in the treatment of tinnitus, as it can bind to the same interaction site as the tiotropium.