Comprehensive computational insights on the conformations, electronic properties and binding mechanism of mescaline: A hallucinogenic molecule

Abstract

In the series of computational investigations of hallucinogenic compounds particularly in unraveling their conformational aspects, mescaline is taken up in this report after having studied psilocybin and psilocin. Six conformers were identified from the relaxed scan of the dihedral angles of which two were taken up for studying their chemical properties. The two low energy conformers differed by about 0.5 kcal.mol-1 at B3LYP/cc-pVTZ and 1.5 kcal.mol-1 at CCSD/cc-PVDZ levels of theory, respectively and structurally the two conformers differ by the orientation of the alkyl amine group vis-à-vis the benzene ring via the N–H---π interaction. Natural Bond Orbital calculations unveiled the existence of intra-molecular π → π*, n → π* charge transfers, and some hyperconjugative interactions that significantly enhance the stability of mescaline. Reduced Density Gradient calculations unraveled the occurrence of strong intramolecular N–H---π interaction in the most stable conformer of mescaline. The calculated geometrical parameters and predicted structure of the most stable conformer of mescaline agree significantly well with the earlier reported conformers from X-ray studies of mescaline. The computed λmax in the UV–visible spectrum, peak positions in the proton NMR spectrum, and vibrational modes exhibit excellent agreement with the previously reported experimental findings. Moreover, we utilized molecular docking and molecular dynamics simulations to elucidate the binding mode and molecular mechanism of mescaline in comparison to other hallucinogenic molecules. Our findings revealed that mescaline displayed a favorable binding energy and induced essential conformational changes, indicating a potential common mechanism of action shared with psilocybin, another hallucinogenic compound.