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

Metabolic syndrome is considered the precursor of type 2 diabetes mellitus. Tuberculosis is a leading infection that constitutes a global threat remaining a major cause of morbi-mortality in developing countries. People with type 2 diabetes mellitus are more likely to suffer from infection with Mycobacterium tuberculosis. For both type 2 diabetes mellitus and tuberculosis, there is pulmonary production of anti-inflammatory glucocorticoids mediated by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal hormone dehydroepiandrosterone (DHEA) counteracts the glucocorticoid effects of cytokine production due to the inhibition of 11β-HSD1. Late advanced tuberculosis has been associated with the suppression of the Th1 response, evidenced by a high ratio of cortisol/DHEA. In a murine model of metabolic syndrome, we determined whether DHEA treatment modifies the pro-inflammatory cytokines due to the inhibition of the 11β-HSD1 expression. Since macrophages express 11β-HSD1, our second goal was incubating them with DHEA and Mycobacterium tuberculosis to show that the microbicide effect was increased by DHEA. Enoyl-acyl carrier protein reductase (InhA) is an essential enzyme of Mycobacterium tuberculosis involved in the mycolic acid synthesis. Because 11β-HSD1 and InhA are members of a short-chain dehydrogenase/reductase family of enzymes, we hypothesize that DHEA could be an antagonist of InhA. Our results demonstrate that DHEA has a direct microbicide effect against Mycobacterium tuberculosis; this effect was supported by in silico docking analysis and the molecular dynamic simulation studies between DHEA and InhA. Thus, DHEA increases the production of pro-inflammatory cytokines in the lung, inactivates GC by 11β-HSD1, and inhibits mycobacterial InhA. The multiple functions of DHEA suggest that this hormone or its synthetic analogs could be an efficient co-adjuvant for tuberculosis treatment.