Functionalization of lead compounds to create analogs is a challenging step in discovering new molecules with desired properties and it is conducted throughout the chemical industry, including pharmaceuticals and agrochemicals. The process can be time-consuming and expensive, requiring expert intuition and experience. To help address synthesis planning challenges in late-stage functionalization, we have developed a molecular similarity approach that proposes single-step functionalization reactions based on analogy to precedent reactions. The developed approach mimics reaction strategies and suggests co-reactants defined implicitly by a corpus of known reactions. Using 348 k reactions from the patent literature as a knowledge base, the recorded products or close analogs are among the top 20 proposed products in 74% of ∼44 k test reactions. The combinatorial growth inherent in recursive applications of the tool allows the enumeration of chemical libraries surrounding a target compound of interest. Moreover, each step of the resulting library synthesis leverages common chemical transformations reported in the literature accessible to most chemists.
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http://dx.doi.org/10.1039/d4sc00523f | DOI Listing |
J Chem Inf Model
December 2024
Orion Pharma, Orionintie 1A, 02101 Espoo, Finland.
Given the size of the relevant chemical space for drug discovery, working with fully enumerated compound libraries (especially in three-dimensional (3D)) is unfeasible. Nonenumerated virtual chemical spaces are a practical solution to this issue, where compounds are described as building blocks which are then connected by rules. One concrete example of such is the BioSolveIT chemical spaces file format (.
View Article and Find Full Text PDFEnviron Sci Technol
December 2024
Department of Environmental Health Science, Yale School of Public Health, New Haven, Connecticut 06511, United States.
Per- and polyfluoroalkyl substances (PFAS) are widely used persistent synthetic chemicals that have been linked to adverse health effects. While the behavior of PFAS has been evaluated in the environment, our understanding of reaction products in mammalian systems is limited. This study identified biological PFAS transformation products and generated mass spectral libraries to facilitate an automated search and identification.
View Article and Find Full Text PDFJ Biomol Struct Dyn
December 2024
Laboratory of Molecular Modeling and Anticancer Drug Development. Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
In about 85% of cancer malignancies, replicative immortality caused by increased telomerase activity makes it an attractive target for developing anticancer therapeutics. However, the lack of approved small-molecule inhibitors rooted in the structural ambiguity of telomerase has impeded drug development for decades. In this study, we have exploited the FVYL pocket in the thumb domain, which plays a key role in the enzyme's processivity.
View Article and Find Full Text PDFAdv Mater
December 2024
Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan.
High-entropy-alloy (HEA) nanocrystals hold immense potential for catalysis, offering virtually unlimited alloy combinations through the inclusion of at least five constituent elements in varying ratios. However, general and effective strategies for synthesizing libraries of HEA nanocrystals with controlled surface atomic structures remain scarce. In this study, a transferable strategy for developing a library of facet-controlled seed@HEA nanocrystals through seed-mediated growth is presented.
View Article and Find Full Text PDFJ Am Chem Soc
December 2024
Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada.
Genetically encoded libraries (GEL) are increasingly being used for the discovery of ligands for "undruggable" targets that cannot be addressed with small molecules. Foundational GEL platforms like phage-, yeast-, ribosome-, and mRNA-display have enabled the display of libraries composed of 20 natural amino acids (20AA). Unnatural amino acids (UAA) and chemical post-translational modification (cPTM) expanded GEL beyond the 20AA space to yield unnatural linear, cyclic, and bicyclic peptides.
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