Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3

Melatonin exhibits extraordinary diversity in terms of its functions and distribution. When discovered, it was thought to be uniquely of pineal gland origin. Subsequently, melatonin synthesis was identified in a variety of organs and recently it was shown to be produced in the mitochondria. Since mitochondria exist in every cell, with a few exceptions, it means that every vertebrate, invertebrate, and plant cell producesmelatonin. The mitochondrial synthesis ofmelatonin is not photoperiod-dependent, but itmay be inducible under conditions of stress. Mitochondria-produced melatonin is not released into the systemic circulation, but rather is used primarily in its cell of origin. Melatonin’s functions in the mitochondria are highly diverse, not unlike those of sirtuin 3 (SIRT3). SIRT3 is an NAD+-dependent deacetylase which regulates, among many functions, the redox state of the mitochondria. Recent data proves that melatonin and SIRT3 post-translationally collaborate in regulating free radical generation and removal from mitochondria. Since melatonin and SIRT3 have cohabitated in the mitochondria for many eons, we predict that these molecules interact in many other ways to control mitochondrial physiology. It is predicted that these mutual functions will be intensely investigated in the next decade and importantly, we assume that the findings will have significant applications for preventing/delaying some age-related diseases and aging itself

Interacción de la catecol o-metiltransferasa (COMT) con diversos inhibidores evaluada mediante cálculos computacionales

En este trabajo se estudió la interacción de la Catecol O-metiltransferasa (COMT) con diferentes inhibidores. Dado que la COMT es la enzima responsable de la degradación de catecolaminas y un blanco terapéutico importante en enfermedades neurodegenerativas. En este trabajo, exploramos el reconocimiento molecular entre COMT y dos tipos de inhibidores que presentan propiedades antioxidantes (IIcD y derivado de melatonina), por lo que sirven de protección ante el estrés oxidativo, y fueron comparados con los inhibidores por excelencia de la enzima. El análisis principal se centró en estudios de acoplamiento molecular para cada sistema propuesto y en la determinación de la energía libre de unión de las interacciones. Los resultados indicaron que la interacción de COMT-inhibidor está gobernada por las contribuciones hidrofóbicas, lo cual concuerda con lo reportado en la literatura. Y se comprobó que el IIcD, inhibidor modelado computacionalmente y con características antioxidantes, posee una mejor unión con la COMT.In this work the interaction of Catechol O-methyltransferase (COMT) with different inhibitors was studied. Since COMT is the enzyme responsible for the degradation of catecholamines and an important therapeutic target in neurodegenerative diseases. In this work, we explore the molecular recognition between COMT and two types of inhibitors that have antioxidant properties (IIcD and melatonin derivative), so they serve as protection against oxidative stress, and were compared with the inhibitors par excellence of the enzyme. The main analysis focused in docking studies for each proposed system and in the determination of the binding free energy of the interactions. The results indicated that the interaction of COMT-inhibitor is governed by hydrophobic contributions, which is consistent with that reported in the literature. And it was found that IIcD, an inhibitor computationally modeled and with antioxidant characteristics, has a better binding with COMT

Phenolic Melatonin-Related Compounds: Their Role as Chemical Protectors against Oxidative Stress

There is currently no doubt about the serious threat that oxidative stress (OS) poses to human health. Therefore, a crucial strategy to maintain a good health status is to identify molecules capable of offering protection against OS through chemical routes. Based on the known efficiency of the phenolic and melatonin (MLT) families of compounds as antioxidants, it is logical to assume that phenolic MLT-related compounds should be (at least) equally efficient. Unfortunately, they have been less investigated than phenols, MLT and its non-phenolic metabolites in this context. The evidence reviewed here strongly suggests that MLT phenolic derivatives can act as both primary and secondary antioxidants, exerting their protection through diverse chemical routes. They all seem to be better free radical scavengers than MLT and Trolox, while some of them also surpass ascorbic acid and resveratrol. However, there are still many aspects that deserve further investigations for this kind of compounds

Potentiating the Benefits of Melatonin through Chemical Functionalization: Possible Impact on Multifactorial Neurodegenerative Disorders

Although melatonin is an astonishing molecule, it is possible that chemistry will help in the discovery of new compounds derived from it that may exceed our expectations regarding antioxidant protection and perhaps even neuroprotection. This review briefly summarizes the significant amount of data gathered to date regarding the multiple health benefits of melatonin and related compounds. This review also highlights some of the most recent directions in the discovery of multifunctional pharmaceuticals intended to act as one-molecule multiple-target drugs with potential use in multifactorial diseases, including neurodegenerative disorders. Herein, we discuss the beneficial activities of melatonin derivatives reported to date, in addition to computational strategies to rationally design new derivatives by functionalization of the melatonin molecular framework. It is hoped that this review will promote more investigations on the subject from both experimental and theoretical perspectives

Output-files-pka-COOH

All the output files for the calculations of pKa values.<br

Data-016221.xlsx

Excel file with all the calculated pKa values<br

Methanol formation

Enthalpies and Gibbs free energies of the chemical routes yielding methanol (in gas phase) in the ISM at different temperatures and pressures