Cheminformatic Analysis of Core-Atom Transformations in Pharmaceutically Relevant Heteroaromatics
G. Logan Bartholomew, Lucas J. Karas, Reilly M. Eason, Charles S. Yeung, Matthew S. Sigman, Richmond Sarpong
Abstract
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.