Selective Modulation of Orexinergic Receptors by Neem-Derived Phytochemicals: Computational Analysis of Structure-Activity Relationships

Orexinergic system dysfunction is the fundamental basis for several neurological illnesses like narcolepsy, insomnia, and drug dependency, yet none of the existing medications are subtype receptor specific. This study examines 124 chemicals from neem to determine if they can be utilised as specific orexinergic receptor modulators using advanced computational methods. The methodology includes detailed clustering, pharmacophoric interaction, pharmacokinetic, statistical, and clustering analyses. Molecular property profiling indicated the majority of the compounds exhibit excellent drug-like qualities (MW 350-450 Da, LogP 0-2), while principal component analysis captured 100 % structural variability between two components (92. 5 % and 7. 5 %, respectively). Molecular docking simulations indicated selective binding to the 6V9S receptor (-11. 3 to -4 kcal/mol) over 4S0V (-9. 7 to -4 kcal/mol). Lead compounds NeemPDB₁0257 (Tirucallol) (-11. 3 kcal/mol) and NeemPDB₁2072821 ( (5 R, 7 R, 8 R, 9 R, 10 R, 13S, 17 R) -17- (2-methoxy-5-oxo-4, 4, 8, 10, 13-pentamethyl-3-oxo-5, 6, 7, 9, 11, 12, 16, 17-octahydrocyclopenta[aphenanthren-7-yl] acetate) were particularly 6V9S selective (>2 kcal/mol difference), whereas NeemPDB₁0160319 ( (4S, 4aS, 5S, 10S, 13S, 14S, 17-4, 4, 10, 13, 14-pentam -1, 2, 3, 5, 6, 7, 11, 12, 15, 17-decahydrocyclopentaaphenanthren-16-one) was most sensitive towards 4S0V. Two top-ranked compound families were discovered by hierarchical cluster analysis with a distance requirement of 35 units, and receptor-specific dendrograms revealed distinctive subcluster branching patterns (4S0V: 5. 5 and 6. 7 unit subclusters; 6V9S: 7. 1 and 7. 2 unit subclusters). Interaction pattern (heatmap analysis) identified major interaction hotspots, including TYR348, TRP120, PHE227, and HIS350. NeemPDB₁63184214 (Meliatetraolenone) specifically targeted ASN318 in 6V9S, while NeemPDB₅4580354 (7-Benzoylnimbocinol) favored interaction with GLN134 in 4S0V (>90 interactions). These findings dispute the "one-pharmacophore" theory for orexinergic modulators, showing that intentional functionalization of NEM templates can deliver subtype-selective treatments with maximal sleep-wake modulation and low off-target effects.