Exploring naringenin-clozapine combination for synergistic antipsychotic action: An in-silico study

Abstract

Naringenin has natural origins with reported antioxidant and neuromodulator properties, and clozapine is a prominent atypical antipsychotic with known dopaminergic and serotonergic mechanisms. Through molecular docking studies, interaction profiling, hydrophobicity analysis, ADMET simulation, toxicity prediction, and protein-protein interaction studies, a combined in-silico strategy was applied for the assessment of the ligand combination Clozapine-Naringenin on Dopamine D2 (DRD2) and Serotonin 5-HT2A (HTR2A) receptors. The two ligands moderately docked into the DRD2 and HTR2A receptor binding pockets with a binding energy of –7.5 kcal/mol and –9.9 kcal/mol respectively, strongly suggesting the ligands' ability to stably interact and reside in the two GPCR binding pockets. Hydrogen bonding interactions were strongly evident between Tyr370, Asn363, and Ser181 in HTR2A and between Arg1096 and Tyr1088 in DRD2. In addition, hydrophobic and π-alkyl interactions were evident and widespread. The characteristic seven-helix structure for all GPCR proteins was supported by hydrophobicity studies, giving credit to the validity and authenticity of the structure for both proteins. As per the model predictions from Swiss-ADME, the compound exhibits excellent oral and overall drug-likeness but has restricted blood-brain barrier penetration with considerable inhibition of CYP enzymes; this indicates possible PK interactions. It belongs to GHS class 4 with an LD50 value of 517 mg/kg. DRD2 and HTR2A were found to be the major signaling hotspots according to protein interaction network study. The Clozapine - Naringenin drug combination is a promising multi-target molecule.