DFT calculations, molecular docking, binding free energy analysis and cytotoxicity assay of 7,7-dimethylaporphine alkaloids with methylenedioxy ring in positions 1 and 2

In this paper, we present a comprehensive characterization of three 7,7-dimethylaporphine alkaloids at a molecular quantum mechanical level using Density Functional Theory (DFT) with the B3LYP/6-311G(2d,p) basis set. These alkaloids have a methylenedioxy group in positions 1 and 2, differing from each other only by the presence or absence of one OCH3 group, with the influence of this group on the properties of the investigated alkaloids being the object of study in this research. The accuracy of our findings is validated by comparing the infrared (IR) and UV-Visible (UV-Vis) spectra with experimental data previously reported by one of the authors. Theoretical geometry optimization data were further assessed against X-ray data from related structures in the literature, revealing close agreement. Additionally, various quantum properties, such as Natural Bond Orbitals (NBOs), HOMO-LUMO energy gap, mapped Molecular Electrostatic Potential (MEP) surface calculation, first and second order hyperpolarizabilities, were evaluated at the same calculation level. To understand the interactions between the alkaloids and important biological targets, molecular dynamics simulations were carried out using Gromacs 2019 software. The focus was on investigating the MM/PBSA binding free energies at the active sites of human Topoisomerase I DNA, Candida Albicans Dihydrofolate Reductase, Acetylcholinesterase, and Spike SARSCoV-2. These results were compared to those obtained from molecular docking studies performed with the alkaloids at the same active sites. Remarkably, alkaloid 2, lacking OCH3 substituents, demonstrated the highest inhibitory potential for three out of the four enzymes, excluding C. Albicans according to docking results, which was subsequently confirmed through cytotoxicity experiments. These findings shed light on the molecular basis for the observed differences in the alkaloids' biological activities and contribute to the design of potential therapeutic agents targeting these enzymes.