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The use of pharmaceuticals to treat Major Depressive Disorder (MDD) has several drawbacks, including severe side effects. Natural compounds with great efficacy and few side effects are in high demand due to the global rise in MDD and ineffective treatment. Yohimbine, a natural compound, has been used to treat various ailments, including neurological conditions, since ancient times. Serotonergic neurotransmission plays a crucial role in the pathogenesis of depression; thus, serotonergic receptor agonist/antagonistic drugs are promising anti-depressants. Yohimbine was investigated in this study to determine its antidepressant activity using molecular docking and pharmacokinetic analyses. Additionally, the in silico mutational study was carried out to understand the increase in therapeutic efficiency using site-directed mutagenesis. Conformational changes and fluctuations occurring during wild type and mutant serotonergic receptor, 5-hydroxytryptamine receptors 1A (5HT1A) and yohimbine were assessed by molecular dynamics MD simulation studies. Yohimbine was found to satisfy all the parameters for drug-likeness and pharmacokinetics analysis. It was found to possess a good dock score and hydrogen-bond interactions with wild type 5HT1A structure. Our findings elaborate the substantial efficacy of yohimbine against MDD; however, further bench work studies may be carried out to prove the same.