Integrating classical and quantum mechanics in melatonin receptors for structure-guided drug design

Although melatonin receptor agonists are acknowledged for their therapeutic potential for managing sleep problems, the structural optimization of these compounds is made challenging by variations in crystallographic data. This study aims to improve the structure of the melatonin receptor type 1 and ramelteon (MT1-RMT) complex and propose a new melatonin receptor agonist with an enhanced binding affinity. Molecular dynamics (MD) simulations have been used to improve the experimental MT1-RMT complex, followed by quantum-mechanical (QM) calculations employing density functional theory (DFT) to assess ligand–receptor interactions. The MD simulations effectively optimized the MT1-RMT complex, resulting in a conformation that was consistent with the experimental binding affinities. The QM calculations validated the improved binding affinity, and additional structural insights facilitated the rational design of a new agonist, N-[2-(5-methoxy-2-phenyl-1H-indol-3-yl)ethyl]propanamide (MPI), which exhibited better affinity for the MT1 and melatonin receptor type 2 (MT2) receptors. These findings suggest that MD-based refinement enhances the precision of protein–ligand complex models and that MPI is a suitable candidate for future pharmaceutical development. Subsequent research should examine the pharmacokinetic characteristics and in vivo effectiveness of MPI.