Food Chemicals and Epigenetic Targets: An Epi Food Chemical Database.

There is increasing awareness of epigenetics's importance in understanding disease etiologies and developing novel therapeutics. An increasing number of publications in the past few years reflect the renewed interest in epigenetic processes and their relationship with food chemicals. However, there needs to be a recent study that accounts for the most recent advances in the area by associating the chemical structures of food and natural product components with their biological activity. Here, we analyze the status of food chemicals and their intersection with natural products in epigenetic research. Using chemoinformatics tools, we compared quantitatively the chemical contents, structural diversity, and coverage in the chemical space of food chemicals with reported epigenetic activity. As part of this work, we built and curated a compound database of food and natural product chemicals annotated with structural information, an epigenetic target activity profile, and the main source of the food chemical or natural product, among other relevant features. The compounds are cross-linked with identifiers from other major public databases such as FooDB and the collection of open natural products, COCONUT. The compound database, the "Epi Food Chemical Database", is accessible in HTML and CSV formats at https://github.com/DIFACQUIM/Epi_food_Chemical_Database.

Diversity and Chemical Library Networks of Large Data Sets.

The quantification of chemical diversity has many applications in drug discovery, organic chemistry, food, and natural product chemistry, to name a few. As the size of the chemical space is expanding rapidly, it is imperative to develop efficient methods to quantify the diversity of large and ultralarge chemical libraries and visualize their mutual relationships in chemical space. Herein, we show an application of our recently introduced extended similarity indices to measure the fingerprint-based diversity of 19 chemical libraries typically used in drug discovery and natural products research with over 18 million compounds. Based on this concept, we introduce the Chemical Library Networks (CLNs) as a general and efficient framework to represent visually the chemical space of large chemical libraries providing a global perspective of the relation between the libraries. For the 19 compound libraries explored in this work, it was found that the (extended) Tanimoto index offers the best description of extended similarity in combination with RDKit fingerprints. CLNs are general and can be explored with any structure representation and similarity coefficient for large chemical libraries.

Chemoinformatic Characterization of Synthetic Screening Libraries Focused on Epigenetic Targets.

The importance of epigenetic drug and probe discovery is on the rise. This is not only paramount to identify and develop therapeutic treatments associated with epigenetic processes but also to understand the underlying epigenetic mechanisms involved in biological processes. To this end, chemical vendors have been developing synthetic compound libraries focused on epigenetic targets to increase the probabilities of identifying promising starting points for drug or probe candidates. However, the chemical contents of these data sets, the distribution of their physicochemical properties, and diversity remain unknown. To fill this gap and make this information available to the scientific community, we report a comprehensive analysis of eleven libraries focused on epigenetic targets containing more than 50,000 compounds. We used well-validated chemoinformatics approaches to characterize these sets, including novel methods such as automated detection of analog series and visual representations of the chemical space based on Constellation Plots and Chemical Library Networks. This work will guide the efforts of experimental groups working on high-throughput and medium-throughput screening of epigenetic-focused libraries. The outcome of this work can also be used as a reference to design and describe novel focused epigenetic libraries.

Towards the De Novo Design of HIV-1 Protease Inhibitors Based on Natural Products.

Acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available in the supplementary material.

Expanding the Structural Diversity of DNA Methyltransferase Inhibitors.

Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.

A pilot study to record visual evoked potentials during prone spine surgery using the SightSaver™ photic visual stimulator.

This is a pilot study to assess the clinical safety and efficacy of recording real-time flash visual evoked potentials (VEPs) using the SightSaver TM Visual Stimulator mask during prone spine surgery. A prospective, observational pilot study. Twenty patients presenting for spine surgery (microdiscectomy, 1-2 level lumbar fusion, or > 2 levels thoraco-lumbar fusion) were enrolled. The SightSaver™ Visual Stimulator™ was used to elicit VEPs throughout surgery. Somatosensory evoked potentials (SSEPs) were simultaneously recorded. All patients underwent general anesthesia with a combination of intravenous and inhaled agents. The presence, absence, and changes in VEP were qualitatively analyzed. Reproducible VEPs were elicited in 18/20 patients (36/40 eyes). VEPs were exquisitely sensitive to changes in anesthesia and decayed with rising MAC of isoflurane and/or N2O. Decrements in VEPs were observed without concomitant changes in SSEPs. The mask was simple to apply and use and was not associated with adverse effects. The SightSaver™ mask represents an emerging technology for monitoring developing visual insults during surgery. The definitive applications remain to be determined, but likely include use in select patients and/or surgeries. Here, we have validated the device as safe and effective, and show that VEPs can be recorded in real time under general anesthesia in the prone position. Future studies should be directed towards understanding the ideal anesthetic regimen to facilitate stable VEP recording during prone spine surgery.

Poly(p-hydroxystyrene) grafted polystyrene nanospheres: excellent hosts for silver and ruthenium nanoparticles.

A novel approach is described for the preparation of surface functionalized micro- and nanobeads using one pot synthesis by a core-shell method. Monodisperse poly(p-hydroxystyrene) is successfully prepared by grafting the p-acetoxystyrene monomer during the last 30 min of the fabrication of polystyrene bead core by emulsifier-free emulsion polymerization followed by hydrolysis of the acetoxy group by a base. The size of the resulting beads is dictated mostly by the size of the core. Hydroxyl derivatized polystyrene microspheres have been found useful as a high surface area and stable support for anchoring catalytically active silver and ruthenium nanoparticles. The bead formation, surface functionalization, and coating with metal nanoparticles have been studied using scanning electron microscopy, transmission electron microscopy, energy dispersive x-ray spectrometry, Fourier transform infrared spectrometry, and Auger analysis.