Design of new reversible and selective inhibitors of monoamine oxidase A and a comparison with drugs already approved

Abstract

Background Monoamine oxidase (MAO) is an enzyme that has been targeted pharmacologically for the treatment of depression and neurodegenerative diseases such as Parkinson's disease. To avoid side effects, drugs currently in use must selectively target either of the enzyme's two isoforms, A or B. In this study, we designed molecules derived from chalcone as potential reversible and selective inhibitors of isoform A of the MAO enzyme. Results Ten thousand one hundred compounds were designed and screened using molecular docking, considering the pharmacokinetic processes of chemical absorption, distribution, metabolism, and excretion. Density functional theory calculations were performed for the main ligands to evaluate their reactivity. Six drugs qualified as reversible and irreversible inhibitors of both isoform A and isoform B. Among these, molecule 356 was found to be a reversible inhibitor with the best performance in selectively targeting isoform A of the MAO enzyme. The interaction stability of ligand 356 in the isoform A binding site was confirmed by molecular dynamics. One hydrogen bond was found between the ligand and the cofactor, and up to six hydrogen bonds were formed between the ligand and the protein. Conclusions We selected a drug model (molecule 356) for its high affinity to isoform A over isoform B of the MAO enzyme. This proposal should decrease experimental costs in drug testing for neurodegenerative diseases. Therefore, our silico design of a reversible inhibitor of isoform A of enzyme monoamine oxidase can be used in further experimental designs of novel drugs with minimal side effects. Graphical Abstract

A Combined Experimental and Computational Study of Novel Benzotriazinone Carboxamides as Alpha-Glucosidase Inhibitors

“…Ionization potential (I) is the amount of energy required to remove an electron from an isolated atom or molecule, and its higher value indicates stability. In series, compound 14k showed the lowest ionization potential value, illustrating the reactive nature of these molecules [ 33 ]. The highest value of electron affinity in 14k and 14l depicts their tendency to accept electrons ( Table 4 ).…”

“…The highest value of electron affinity in 14k and 14l depicts their tendency to accept electrons ( Table 4 ). The chemical hardness (η) value shows the resistance of a molecule to changing its electronic distribution in a chemical reaction, and chemical softness (S) indicates an easily changeable electronic structure [ 33 ]. The lowest value of chemical hardness of 14k shows its reactive nature towards biomolecules whereas the highest value of 14d indicates poor inhibition potency.…”