Dual Inhibition of SERT and MAO-A by a Novel Phytoconstituent from Premna esculenta: A Convergence of Behavioral, Computational, and ADMET Studies

Depression is a common psychiatric problem that coexists with several neurodegenerative diseases, including Alzheimer's disease (AD), which was the most significant pathophysiological mechanism, including imbalance of neurotransmitters and oxidative stress. They are commonly linked to negative sides like adverse effects and resistance to treatment, but the current antidepressants, like SERT and MAO-A, are good. This research paper examined the antidepressant property of ethanolic Premna esculenta (EEPE), a medicinal plant, through a multidimensional study involving phytochemical, behavioral studies with established murine models, specifically the Forced Swim and Tail Suspension Tests, where the extracts substantially reduced immobility in a dose-dependent manner under varied conditions, and in silico studies. Also, an acute toxicity test was conducted, and it revealed the safety of using different doses. In terms of docking, GC-MS analysis recognized 1,2,3,4-Tetrahydro-3-(phenylacetamido)quinoline as a lead compound, which had strong dual binding potential with serotonin transporter and monoamine oxidase A docks. Additional insights on ADMET and ProToxII showed a favourable blood-brain barrier permeability and lower toxicity than the conventional drugs. Remarkably, anxiolytic and neuroprotective properties of relevance to Alzheimer's disease were also proposed by the PASS prediction regarding THPAC. Lastly, density functional theory (DFT) calculations confirmed this observation with a low value of HOMO-LUMO gap and molecular softness, leading features that are indicative of a high degree of biological interaction. Altogether, the findings allow one to suppose that EEPE can become a multifunctional and safe potential agent in treating depression and even neurodegeneration, due to the presence of THPAC.