Molecular Docking, MM-GBSA, and Molecular Dynamics Approach: 5-MeO-DMT Analogues as Potential Antidepressants.
Archives of Razi Institute October 1, 2023 Rajagopal Kalirajan, Khare Rishabh, Jupudi Srikanth et al.
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.