Computational chemistry using Density Functional Theory (DFT) at the BP86/Def2-TZVP level reveals that the molecular geometry of hallucinogens such as psilocybin and mescaline derivatives is crucial for their activity. Among 13 compounds studied, all except tin and lead derivatives show considerable stability for laboratory synthesis. Geometry and reactivity descriptors are important tools for understanding the activity of these compounds, which have potential as drugs for various conditions.
Depression affects about 5% of the global population. The monoamine-deficiency hypothesis links depression to depletion of neurotransmitters like serotonin, norepinephrine, and dopamine. Serotonin 5-HT2A receptors are abundant in brain regions involved in memory and thought. A computational study compared the hallucinogenic psychedelic 5-MeO-DMT with its non-hallucinogenic analog 6-MeO-DMT for binding to the 5-HT2A receptor. Molecular docking using Schrodinger's Suite 2020-1 gave XP gscores of -8.01 kcal/mol for 5-MeO-DMT and -7.43 kcal/mol for 6-MeO-DMT. MM-GBSA binding free energies were -39.20 kcal/mol for 5-MeO-DMT and 52.41 kcal/mol for 6-MeO-DMT, with 6-MeO-DMT showing superior scores. Additional computational analyses included radius of gyration, molecular surface area, solvent-accessible surface area, and polar surface area.