2025/03/07 by G. Logan Bartholomew, Lucas J. Karas, Reilly M. Eason +3 · 1 voice
Computer Science · Chemistry · Biochemistry, Genetics and Molecular Biology · #Computational Drug Discovery Methods #Click Chemistry and Applications #Chemical Synthesis and Analysis
paper · doi:10.1021/acs.jmedchem.4c02839
Heteroaromatics are the basis for many pharmaceuticals. The ability to modify these structures through selective core-atom transformations, or "skeletal edits", can dramatically expand the landscape for drug discovery and development. However, despite the importance of core-atom modifications, the quantitative impact of such transformations on accessible chemical space remains undefined. Here, we report a cheminformatic platform to analyze which skeletal edits would most increase access to novel chemical space. This study underscores the significance of emerging single and multiple core-atom transformations of heteroaromatics in enhancing chemical diversity, for example, at a late-stage of a drug discovery campaign. Our findings provide a quantitative framework for prioritizing core-atom modifications in heteroaromatic structural motifs, calling for the development of new methods to achieve these types of transformations.