Recent analysis of marketed drugs and commercial vendor libraries commonly used in high-throughput screening suggest that the medicinally relevant chemical space may be expanded to unexplored regions. Novel regions of the chemical space can be conveniently explored with structurally unique molecules with increased complexity, as compared to commonly used screening libraries, and balanced physicochemical properties. In light of the recent studies showing that more complex compounds have better chances to succeed at various stages of the drug discovery process, herein we report a comprehensive comparison of a large in-house collection assembled from 30 small-molecule combinatorial libraries with emphasis on assessing molecular complexity. We used a well-established and intuitive approach to quantify stereochemical and shape complexity. The combinatorial libraries analyzed in this work have been successfully used over the past 20 years to identify novel bioactive compounds across different therapeutic areas. We also analyzed the complexity, distribution of physicochemical properties and structural diversity of the Traditional Chinese Medicine (TCM) database, a large publicly available collection of natural products, approved drugs, and other commonly used screening collections. We show that in-house combinatorial libraries and natural products from TCM are suitable sources to expand the traditional relevant medicinal chemistry space .

Interrogating novel regions of chemical space with complex molecular libraries

244th National Meeting (2012)

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