Theoretical Study of Monoamine Oxidase B Inhibitors as Drug Candidates for Treatment of Parkinson's Disease.

BACKGROUND: Drugs used for Parkinson's disease (PD) are mainly responsible for only relieving major symptoms, but may present several side effects that are typical of such pharmacological treatment. METHODS: This study aimed to use in silico methods for drug designing inhibitors of the PD therapeutic target, monoamine oxidase B (MAO-B). Thus, 20 MAO-B inhibitors from the BindingDB database were selected followed by a calculation of their descriptors at DFT B3LYP/6-31G** level of theory. RESULTS: Statistical analysis considering a Pearson correlation matrix led to the selection of electrophilicity index as a descriptor related to the biological activity of inhibitors. Furthermore, based on the prediction of suitable ADME/Tox properties, the molecule CID 54583085 was selected as a template to carry out structural modifications to obtain 3 analogues, whereas molecules B and C showed significant improvement in mutagenicity and carcinogenicity, in relation to the template. CONCLUSION: Thus, it is concluded that the proposed modifications led us to satisfactory results, since there was an improvement in the toxicological properties of molecules, however, further studies must be carried out to evaluate their biological activities as possible MAO-B inhibitors for PD treatment.

Proposition of Potential GSK-3ß Inhibitors for the Treatment of Alzheimer's Disease: A Molecular Modeling Study.

INTRODUCTION: The enzyme Glycogen Synthase Kinase 3-ß (GSK-3ß) is related to neuronal cell degeneration, representing a promising target to treat Alzheimer's Disease (AD). METHODS: In this work, we performed a molecular modeling study of existing GSK-3ß inhibitors by means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic viability. RESULTS: In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it demonstrated to bear relevant structural groups able to interact with GSK-3ß, and also presented favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition of hERG and medium prediction of synthetic viability. CONCLUSION: It is concluded that the analogues of GSK-3ß inhibitors were optimized in relation to the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising drug candidates for AD treatment.