An Update to Diversity Space and an Examination of its Utility for Library Optimization after a High-throughput Screen
Sara H. Fitzgerald
Degree Award Date
chemical libraries, public domain, high-throughput antiviral screen
To assess the novelty of chemical libraries in the public domain, a Diversity Space analysis was conducted for the libraries published in the year 2006, as assembled by Dolle et al. in the Journal of Combinatorial Chemistry's annual comprehensive review. Conformations were generated for each three-point diverse library in Discovery Studio, allowing a 10 kcal energy range from the global minimum conformation. These libraries were then compared against the data previously produced for the Diversity Space analysis of the 1992-2005 libraries. The distances between the R-groups were used as the basis for comparison, and the results were organized into overlap matrices, which were evaluated for the degree of novelty in the 2006 collection. While significant redundancy is noted, it is promising that approximately one-third of the libraries surveyed access a set of orientations not previously accessed by any former public domain library. Additionally, the full public domain set was compared to libraries that were recently shown to express activity in a high-throughput antiviral screen. Several promising scaffold hopping candidates were identified, which appear to retain many of the orientations preferred by the viral targets while offering more synthetically-tractable alternatives from which to develop the structure-activity relationship.
AbuNada, Ibrahim Y., "An Update to Diversity Space and an Examination of its Utility for Library Optimization after a High-throughput Screen" (2015). Honors Projects. 26.