Molecular Docking, MM-GBSA, and Molecular Dynamics Approach: 5-MeO-DMT Analogues as Potential Antidepressants.

Depression affects an estimated 5% of people worldwide. The monoamine-deficiency hypothesis suggests that a deficiency of neurotransmitters like serotonin contributes to depression. The psychedelic compound 5-MeO-DMT elevates serotonin levels, improving life satisfaction and mindfulness while reducing depression, anxiety, and cortisol, but it has hallucinogenic effects. In this study, 70,000 analogues of 5-MeO-DMT were screened via high-throughput virtual screening and molecular docking against the 5-HT1A receptor. Glide XP docking showed 14 compounds had better binding affinity than 5-MeO-DMT (-7.75 kcal/mol), with Glide scores from -11.41 to -6.53 kcal/mol. MM-GBSA indicated 18 compounds had better binding free energy than the standard. Molecular dynamics simulations over 100 ns identified key stabilizing interactions with residues including Asp116, Phe361, and Trp358.

Study at a glance

Abstract

Since depression is a common mental illness affecting an estimated 5% 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, 5-methoxy-N, N-dimethyltryptamine (5-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 5-MeO-DMT lowers stress biomarkers such as cortisol, it is a psychedelic with hallucinogenic effects. In the present study, analogues of 5-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 5-MeO-DMT analogues as possible antidepressants. We used 70,000 5-MeO-DMT analogues that were sketched using Marvin to conduct a High Throughput Virtual Screening method in hopes of finding potential 5-MeO-DMT analogues against the 5-Hydroxytryptamine 1A receptor (5-HT1AR; 7E2Y.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 21 compounds had Glide gscores ranging from -11.41 to -6.53 kcal/mol. When compared to the standard 5-MeO-DMT with the binding affinity of -7.75 kcal/mol, 14 compounds showed better binding affinity. Furthermore, Molecular Mechanics -Generalised Born and Surface Area solvation (MM-GBSA) indicated a binding free energy range of -63.55 to -35.37 kcal/mol, and 18 compounds showed better binding free energy than standard 5-MeO-DMT (-41.42 kcal/mol). Through ligand binding interactions with Asp116, Phe361, Phe362, Ser190, Ser199, Val117, Trp358, Ala365, Pro369, Ile189, Tyr195, Ala203, Ile167, Tyr390, Cys120, Trp358, Val364, Ala365, and Leu368, these complexes were stabilized, according to the molecular dynamic simulation of 20453/7E2Y in 100ns.