Molecular Insights into the Interaction of Orexin 1 Receptor Antagonists: A Comprehensive Study Using Classical and...

Area of Science:

• Pharmacology
• Computational Chemistry
• Neuroscience

Background:

• Sleep disorders like insomnia and narcolepsy severely affect life quality and health.
• Traditional treatments have limitations like tolerance and dependence.
• The orexinergic system, specifically the orexin 1 receptor (OXR1), is a key target for sleep-wake cycle regulation.

Purpose of the Study:

• To investigate molecular interactions of OXR1 antagonists (daridorexant, lemborexant, suvorexant).
• To provide a molecular basis for designing improved OXR1 antagonists for sleep disorders.

Main Methods:

• Integrated computational approach: molecular dynamics (MD) simulations, density functional theory (DFT) calculations.
• Molecular Fractionation with Conjugate Caps (MFCC) methodology for quantifying ligand-receptor interaction energies.
• Analysis of specific amino acid contributions to binding stability.

Main Results:

• Identified critical residues (GLU204, HIS216, ASN318) for stabilizing OXR1 antagonist binding.
• Observed decreased binding energy with increasing dielectric constants.
• Daridorexant demonstrated the strongest interaction energy via hydrogen bonds and hydrophobic contacts.
• Lemborexant and suvorexant exhibited distinct binding patterns primarily through hydrophobic interactions.

Conclusions:

• Computational methods offer detailed insights into drug-receptor interactions at the atomic level.
• Findings support the rational design of next-generation OXR1 antagonists with enhanced efficacy and safety.
• This research advances targeted therapies for sleep disorders through precise molecular understanding.