This is the last in a three-part series discussing Chemical Diversity in fragment library design. In Part 1, we introduced the concept of diversity in the context of fragment screening libraries. In Part 2, we discussed different measures of diversity and the pros and cons of each in fragment library design.
We view diversity as a measure of the efficiency of the library (hits obtained per compound screen) and the ability to provide of a diverse range of starting points for synthesis. A diverse set of starting points mitigates risk during the optimization process due to scaffold-associated toxicity/pharmacokinetic issues or unforeseen patent conflicts. As such, we view diversity of the compound cores as a primary measure of diversity with slightly different design strategies used for each library.
We define diversity using an internally derived coefficient Zen-DC which is the number of cores in the library divided by the number of unique cores. Cores are defined using the Murcko core definition commonly implemented in cheminformatic software. (Bemis and Murcko, J Med Chem (1996) 39, 2887-2893)
The ZenDC for the overall library is 0.5. By comparison, other commercial libraries such as Chembridge are much lower with Zen-DC of 0.2.
Zen-Library 1 is largely composed of cores commonly found in drugs. Functionality on these drug-like cores is sampled more extensively than in the other libraries and therefore has the lowest ZenDC. Specifically, it has 66 unique Murcko cores and is composed of 352 compounds for a ZenDC of 0.19. The purpose of this library is to sample drug-like fragment space.
Zen-Library 2 brings in more unique cores with additional 3D character. It has a high ZenDC with 145 unique cores being sampled over 192 compounds for a Zen-DC of 0.75. Screening this library gives rise to more unique cores and is an ideal screen to find new starting points for chemistry.
Zen-Opti is covers the properties of Zen-Library1 with drug like cores and Zen-Library2 with slightly more complicated cores in one library. It has 82 unique Murcko cores sampled over 160 compounds for a ZenDC of 0.51.
Zen-Flex is our most unique library. It is an answer to very small and very complicated binding pockets. Instead of locking molecules in a fixed 3D conformation in hopes of fitting a complicated 3D site, Zen-Flex samples non-ring containing compounds and 3D cores with some flexibility. Additional rotatable bonds facilitate access to non-linear sites. We believe these compounds aid in sampling 3D binding pockets and have a higher probability of binding than more complicated and higher molecular weight 3D fragments (despite a potential entropic binding cost). Adding Zen-Flex into a fragment screen brings a new depth of diversity by sampling compounds that may find binding sites not found by ring-containing compounds.
To recap:Zenobia has a focus on core diversity in design of their libraries to provide a broader range of starting points for chemistry and other follow-on studies.