De Novo Design of Inhibitors of DNA Methyltransferase 1: A Critical Comparison of Ligand- and Structure-Based Approaches.

Designing and developing inhibitors against the epigenetic target DNA methyltransferase (DNMT) is an attractive strategy in epigenetic drug discovery. DNMT1 is one of the epigenetic enzymes with significant clinical relevance. Structure-based de novo design is a drug discovery strategy that was used in combination with similarity searching to identify a novel DNMT inhibitor with a novel chemical scaffold and warrants further exploration. This study aimed to continue exploring the potential of de novo design to build epigenetic-focused libraries targeted toward DNMT1. Herein, we report the results of an in-depth and critical comparison of ligand- and structure-based de novo design of screening libraries focused on DNMT1. The newly designed chemical libraries focused on DNMT1 are freely available on GitHub.

Chemical Multiverse and Diversity of Food Chemicals.

Food chemicals have a fundamental role in our lives, with an extended impact on nutrition, disease prevention, and marked economic implications in the food industry. The number of food chemical compounds in public databases has substantially increased in the past few years, which can be characterized using chemoinformatics approaches. We and other groups explored public food chemical libraries containing up to 26,500 compounds. This study aimed to analyze the chemical contents, diversity, and coverage in the chemical space of food chemicals and additives and, from here on, food components. The approach to food components addressed in this study is a public database with more than 70,000 compounds, including those predicted via omics techniques. It was concluded that food components have distinctive physicochemical properties and constitutional descriptors despite sharing many chemical structures with natural products. Food components, on average, have large molecular weights and several apolar structures with saturated hydrocarbons. Compared to reference databases, food component structures have low scaffold and fingerprint-based diversity and high structural complexity, as measured by the fraction of sp3 carbons. These structural features are associated with a large fraction of macronutrients as lipids. Lipids in food components were decompiled by an analysis of the maximum common substructures. The chemical multiverse representation of food chemicals showed a larger coverage of chemical space than natural products and FDA-approved drugs by using different sets of representations.

Advances in the Exploration of the Epigenetic Relevant Chemical Space.

Epigenetic drug discovery is a promising avenue to find therapeutic agents for treating several diseases and developing novel chemical probes for research. In order to identify hit and lead compounds, the chemical space has been explored and screened, generating valuable bioactivity information that can be used for multiple purposes such as prediction of the activity of existing chemicals, e.g., small molecules, guiding the design or optimization of compounds, and expanding the epigenetic relevant chemical space. Herein, we review the chemical spaces explored for epigenetic drug discovery and discuss the advances in using structure-activity relationships stored in public chemogenomic databases. We also review current efforts to chart and identify novel regions of the epigenetic relevant chemical space. In particular, we discuss the development and accessibility of two significant types of compound libraries focused on epigenetic targets: commercially available libraries for screening and targeted chemical libraries using de novo design. In this mini-review, we emphasize inhibitors of DNA methyltransferases.