Computational Investigation of Montelukast and Its Structural Derivatives for Binding Affinity to Dopaminergic and Serotonergic Receptors: Insights from a Comprehensive Molecular Simulation

Background/Objectives: Montelukast (MLK), a leukotriene receptor antagonist, has been associated with neuropsychiatric side effects, raising concerns about its safety. This study aimed to rationally modify MLK’s structure to reduce these risks by optimizing its interactions with dopamine D2 (DRD2) and serotonin 5-HT1A receptors using computational molecular simulation techniques. Methods: A library of MLK derivatives was designed and screened using structural similarity analysis, molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADME-Tox predictions. Structural similarity analysis, based on Tanimoto coefficient fingerprinting, compared MLK derivatives to known neuropsychiatric drugs. Docking was performed to assess initial receptor binding, followed by 100 ns MD simulations to evaluate binding stability. MM/PBSA calculations quantified binding affinities, while ADME-Tox profiling predicted pharmacokinetic and toxicity risks. Results: Several MLK derivatives showed enhanced DRD2 and 5-HT1A binding. MLK_MOD-42 and MLK_MOD-43 emerged as the most promising candidates, exhibiting MM/PBSA binding free energies of −31.92 ± 2.54 kcal/mol and −27.37 ± 2.22 kcal/mol for DRD2 and −30.22 ± 2.29 kcal/mol and −28.19 ± 2.14 kcal/mol for 5-HT1A, respectively. Structural similarity analysis confirmed that these derivatives share key pharmacophoric features with atypical antipsychotics and anxiolytics. ADME-Tox analysis predicted improved oral bioavailability and lower neurotoxicity risks. Conclusions: MLK_MOD-42 and MLK_MOD-43 exhibit optimized receptor interactions, enhanced pharmacokinetics, and lower toxicity risks, making them promising candidates for reducing neuropsychiatric side effects and potential drug repurposing for neuropsychiatric disorders. Further in vitro and in vivo validation is warranted to confirm their therapeutic potential.