Molecular Docking, MM-GBSA, and Molecular Dynamics Approach: ۵-MeO-DMT Analogues as Potential Antidepressants

Since depression is a common mental illness affecting an estimated ۵% of people worldwide, investigators are encouraged to develop effective antidepressants. According to the monoamine-deficiency hypothesis, the underlying pathophysiology of depression is a deficiency of some neurotransmitters (serotonin, norepinephrine, or dopamine) in the central nervous system. The neurotransmitter serotonin has drawn the most attention concerning depression. As per research, ۵-methoxy-N, N-dimethyltryptamine (۵-MeO-DMT) elevates inter-synaptic serotonin levels when administered as a single inhalation of vapor from dried toad secretion and leads to higher life satisfaction, convergent thinking, higher ratings of mindfulness, lower ratings of depression, and anxiety. Furthermore, although ۵-MeO-DMT lowers stress biomarkers such as cortisol, it is a psychedelic with hallucinogenic effects. In the present study, analogues of ۵-MeO-DMT are designed with the hope that they might have better therapeutic activity and lower psychedelic side effects. The current study aimed to look at ۵-MeO-DMT analogues as possible antidepressants. We used ۷۰,۰۰۰ ۵-MeO-DMT analogues that were sketched using Marvin to conduct a High Throughput Virtual Screening method in hopes of finding potential ۵-MeO-DMT analogues against the ۵-Hydroxytryptamine ۱A receptor (۵-HT۱AR; ۷E۲Y.pdb) as an agonist. The prediction of the analogue-protein interaction and the evaluation of the binding affinity is accomplished by employing molecular docking. The Glide XP docking data indicated that a total of ۲۱ compounds had Glide gscores ranging from -۱۱.۴۱ to -۶.۵۳ kcal/mol. When compared to the standard ۵-MeO-DMT with the binding affinity of -۷.۷۵ kcal/mol, ۱۴ compounds showed better binding affinity. Furthermore, Molecular Mechanics -Generalised Born and Surface Area solvation (MM-GBSA) indicated a binding free energy range of -۶۳.۵۵ to -۳۵.۳۷ kcal/mol, and ۱۸ compounds showed better binding free energy than standard ۵-MeO-DMT (-۴۱.۴۲ kcal/mol). Through ligand binding interactions with Asp۱۱۶, Phe۳۶۱, Phe۳۶۲, Ser۱۹۰, Ser۱۹۹, Val۱۱۷, Trp۳۵۸, Ala۳۶۵, Pro۳۶۹, Ile۱۸۹, Tyr۱۹۵, Ala۲۰۳, Ile۱۶۷, Tyr۳۹۰, Cys۱۲۰, Trp۳۵۸, Val۳۶۴, Ala۳۶۵, and Leu۳۶۸, these complexes were stabilized, according to the molecular dynamic simulation of ۲۰۴۵۳/۷E۲Y in ۱۰۰ns.