Unlocking the Therapeutic Potential of DMT’s: Molecular Modelling Insights into Nueropharmacological Mechanisms and Clinical Prospects
Rishabh Khare, K. Rajagopal, Srikanth Jupudi, Preeya Negi, Anuj Kumar Singh, Mohamed H Nafady, T. Emran, Rashu Barua, F. Nainu
Letters in Applied NanoBioScience June 30, 2024 DOI: 10.33263/lianbs132.099 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In silico study Peer reviewed |
|---|---|
| Topics | DMT |
| Key points | 6-MeO-DMT exhibited superior MM-GBSA binding free energy scores compared to 5-MeO-DMT when docked into the 5-HT2A receptor. |
Abstract
Depression is a critical mental ailment as it impacts about 5% of the global population, prompting scientists to create more efficacious antidepressants. The monoamine-deficiency hypothesis suggests that depression is caused by the depletion of certain neurotransmitters like serotonin, norepinephrine, and dopamine in the brain, where serotonin plays the most critical role among all and has been extensively studied in the context of depression. Serotonin 5-hydroxytryptamine 2A receptors (5-HT2ARs) are abundant in the brain, particularly in memory and thought-related regions of the central nervous system. Numerous hallucinogens, antipsychotics, and antidepressants target 5-HT2ARs together with endogenous 5-HT to exert their effects. Research indicates that 5-MeO-DMT increases serotonin levels across nerve cells, leading to enhanced life satisfaction, convergent thinking, mindfulness, and reduced levels of despair and anxiety. A comparative study is conducted to analyze the binding affinity and stability of 5-MeO-DMT, a hallucinogenic psychedelic, in comparison to its non-hallucinogenic analog 6-MeO-DMT through in silico studies. To assess whether 6-MeO-DMT is a viable option for treating depression. 5-MeO-DMT and 6-MeO-DMT were drawn using Marvin software, and molecular docking was conducted using Schrodinger’s Suite 2020-1 to analyze the binding affinity and interaction of the sketched molecules in the active binding pocket of 5-HT2AR. The XP docking data showed the gscores of 5-MeO-DMT (-8.01 kcal/mol) and 6-MeO-DMT (-7.43 kcal/mol). Additionally, MM-GBSA revealed binding free energies (∆Bind) of -39.20 and 52.41 kcal/mol for 5-MeO-DMT and 6-MeO-DMT, respectively, where 6-MeO-DMT exhibited superior scores. Computational analysis were also conducted for other molecular properties, including radius of gyration, molecular surface area, solvent-accessible surface area, and polar surface area.