Abstract
A systematic rational search for newly designed melatonin derivatives, was performed using a computer-assisted protocol. A total of 116 derivatives were generated by adding functional groups (i.e., -OH, -NH2, -SH and -COOH) to the melatonin structure. A selection score (SS) was built to sample the search space, simultaneously considering ADME (absorption, distribution, metabolism, excretion) properties, toxicity and manufacturability (i.e., synthetic accessibility). The search characterized the whole set of designed melatonin derivatives and allowed the selection of a reduced subset of 20 melatonin derivatives that are expected to be the most promising, regarding drug-like behavior. For this subset, several reactivity indices were estimated, as well as their pKa values. According to the gathered data, 5 melatonin derivatives have been identified as the most likely candidates to act as chemical antioxidant (directly scavenging free radicals, by electron transfer and/or H transfer). All of them are predicted to be better for that purpose than melatonin itself or trolox (water soluble vitamin E analog). The findings from this work are expected to motivate further investigations on these molecules, using both theoretical and experimental approaches.
Highlights
Oxidative stress (OS) and chemical agents against it are currently the focus of numerous investigations
Type I are molecules that directly react with free radicals, they are usually referred to as free radical scavengers
It was used to characterize the whole set of designed melatonin derivatives (116 species) and choosing a reduced subset of 20 molecules that are expected to be the most promising, regarding drug-like behavior
Summary
Oxidative stress (OS) and chemical agents against it are currently the focus of numerous investigations. The interest in both, oxidative damage to biomolecules and its prevention by chemical species (usually referred to as antioxidants) is well justified. There is abundant data supporting the protective effects of varied chemicals against OS and associated diseases. Naturally occurring molecules have been the most widely studied in this context, there is an increased interest in designing molecules capable of exerting such protection. Melatonin (N-acetyl-5-methoxytryptamine, Scheme 1) is one of the most comprehensively studied. Some of the melatonin’s features make this molecule a appealing antioxidant:
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