Ascorbic acid (vitamin C) is a water-soluble vitamin and a recognized antioxidant drug that is used topically in dermatology to treat and prevent the changes associated with photoaging, as well as for the treatment of hyperpigmentation. Ascorbic acid has neutralizing properties of free radicals, being able to interact with superoxide, hydroxyl and free oxygen ions, preventing the inflammatory processes, carcinogens, and other processes that accelerate photoaging in the skin. Current research focuses on the search for stable compounds of ascorbic acid and new alternatives for administration in the dermis. Unlike plants and most animals, humans do not have the ability to synthesize our own ascorbic acid due to the deficiency of the enzyme L-gulono-gamma-lactone oxidase, which catalyzes the passage terminal in the ascorbic acid biosynthesis. To deal with this situation, humans obtain this vitamin from the diet and/or vitamin supplements, thus preventing the development of diseases and achieving general well-being. Ascorbic acid is involved in important metabolic functions and is vital for the growth and maintenance of healthy bones, teeth, gums, ligaments, and blood vessels. Ascorbic acid is a very unstable vitamin and is easily oxidized in aqueous solutions and cosmetic formulations. Ascorbic acid is extensively used as an ingredient in anti-aging cosmetic products, as sodium ascorbate or ascorbyl palmitate. This review discusses and describes the potential roles for ascorbic acid in skin health and their clinical applications (antioxidative, photoprotective, anti-aging, and anti-pigmentary effects) of topical ascorbic acid on the skin and main mechanisms of action. Considering the instability and difficulty in administering ascorbic acid, we also discuss the importance of several factors involved in the formulation and stabilization of their topical preparations in this review.
The development of open computational pipelines to accelerate the discovery of treatments for emerging diseases allows finding novel solutions in shorter periods of time. Consensus molecular docking is one of these approaches, and its main purpose is to increase the detection of real actives within virtual screening campaigns. Here we present dockECR, an open consensus docking and ranking protocol that implements the exponential consensus ranking method to prioritize molecular candidates. The protocol uses four open source molecular docking programs: AutoDock Vina, Smina, LeDock and rDock, to rank the molecules. In addition, we introduce a scoring strategy based on the average RMSD obtained from comparing the best poses from each single program to complement the consensus ranking with information about the predicted poses. The protocol was benchmarked using 15 relevant protein targets with known actives and decoys, and applied using the main protease of the SARS-CoV-2 virus. For the application, different crystal structures of the protease, and frames obtained from molecular dynamics simulations were used to dock a library of 79 molecules derived from previously co-crystallized fragments. The ranking obtained with dockECR was used to prioritize eight candidates, which were evaluated in terms of the interactions generated with key residues from the protease. The protocol can be implemented in any virtual screening campaign involving proteins as molecular targets. The dockECR code is publicly available at: https://github.com/rochoa85/dockECR .
During the second half of the 20th century, following structural biology hallmark works on DNA and proteins, biochemists shifted their questions from “what does this molecule look like?” to “how does this process work?”. Prompted by the theoretical and practical developments in computational chemistry, this led to the emergence of biomolecular simulations and, along with the 2013 Nobel Prize in Chemistry, to the development of hybrid QM/MM methods. QM/MM methods are necessary whenever the problem we want to address involves chemical reactivity and/or a change in the system’s electronic structure, with archetypal examples being the studies of an enzyme’s reaction mechanism and a metalloprotein’s active site. In the last decades QM/MM methods have seen an increasing adoption driven by their incorporation in widely used biomolecular simulation software. However, properly setting up a QM/MM simulation is not an easy task, and several issues need to be properly addressed to obtain meaningful results. In the present work, we describe both the theoretical concepts and practical issues that need to be considered when performing QM/MM simulations. We start with a brief historical perspective on the development of these methods and describe when and why QM/MM methods are mandatory. Then we show how to properly select and analyze the performance of the QM level of theory, the QM system size, and the position and type of the boundaries. We show the relevance of performing prior QM model system (or QM cluster) calculations in a vacuum and how to use the corresponding results to adequately calibrate those derived from QM/MM. We also discuss how to prepare the starting structure and how to select an adequate simulation strategy, including those based on geometry optimizations as well as free energy methods. In particular, we focus on the determination of free energy profiles using multiple steered molecular dynamics (MSMD) combined with Jarzynski’s equation. Finally, we describe the results for two illustrative and complementary examples: the reaction performed by chorismate mutase and the study of ligand binding to hemoglobins. Overall, we provide many practical recommendations (or shortcuts) together with important conceptualizations that we hope will encourage more and more researchers to incorporate QM/MM studies into their research projects.
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