July 27, 2017

Why Screen as Mixtures?

In many cases, it is much more efficient to screen as mixtures because it pares down the dataset to a manageable range. One uses screening mixtures by soaking the crystal in a cocktail with multiple ligands. The secret to designing the proper mixture is to ensure that each ligand in the cocktail is differentiable from the other ligands, even at low resolutions. Express-Zen-Core288™ has a very high shape diversity, making it possible to group into shape diverse mixtures that can be distinguished at 2.7Å-3.0Å. 

How Does Zenobia Make it's Mixtures?

Zenobia's mixtures for crystallographic screening contain up to 6 compounds that are highly shape diverse permitting identification of the hit from the shape of the electron density map (Nienaber et al., 2000). For those that are not limited by crystals or beamtime, mixtures of 3 or single compound screening kits are also available for crystallography. Sample mixtures of 6 are depicted below.


July 20, 2017

What is Crystallographic Screening?

Crystallographic screening is a method used to detect ligands that bind to a target protein. What makes this metod special is that it also provides structural data about the binding location and interactions between the ligand and protein. The crystal itself has the protein molecules lined up in an ordered array with large solvent channels so that ligands can soak in and bind to sites on the crystallized protein. This method is exceptionally successful in detecting weakly binding ligands because the protein is highly concentrated in the crystal. Once the crystal has been soaked in the cocktail of ligands, diffraction data are collected and used to calculate an electron density map to determine if any of the ligands bound to the protein. If they do bind, one can tell by a visible positive electron density peak in a difference density map between the putative ligand protein complex and apoprotein. The ligand cocktails should be designed so that each lig...

September 23, 2016

PART 1: What is Chemical Diversity?

This is the first in a three-part series discussing chemical diversity. 

In Part 1, we introduce the concept of diversity in the context of fragment screening libraries.

How does one understand Chemical Diversity?

Merriam-Webster dictionary defines diversity as: “an instance of being composed of differing elements or qualities".

In the context of screening libraries, we refer to chemical diversity as the diversity of the chemical composition for a set of compounds. However, the approaches and criteria for chemical diversity can be as diverse as the libraries themselves! 

Interestingly, despite the strong emphasis placed on library diversity, there is actually no correlation between chemical properties and biological activity reported in the literature (1). 

Why is diversity a defining characteristic of chemical libraries? 

From our point of view, diversity is directly related to the efficiency of the library. This includes coverage of chemical s...

August 3, 2016

The "Guideline of Two"

Over the past decade, a number of rules and calculated metrics have arisen in drug

discovery.  In particular, the Rule of Three (RO3) is most commonly used as a filter to generate a "fragment library" from a larger compound collection.


  • Rules evolve over time to reflect data and experiences

  • Issues can arise from universally applying rules to all situations

Emerging data has shown that a simple filter of compound libraries to generate a "RO3 fragment library" while a good start, may not yield the most efficient and productive screening results and ultimately the most successful clinical candidate.

Based upon the following evidence, we are proposing a Guideline of Two for fragments (GoT Frags) rather than a Rule of Three:

Guideline 1: MW < 200-250

Emerging data since the RO3 was published shows that the average molecular weight of successful drug candidates is in the range of 350.  Recall that lead optimization adds on average about 100 in molecular w...

March 4, 2016


 As fragment screening continues to grow in popularity and establish itself as an integral part of discovery research, the emergence of more and more compounds added to fragment library collections seems to grow exponentially. What once was an efficient means of effectively screening a target to provide information about its drugability or identify the unique building blocks of a clinical candidate, has now become diluted in a pool of tens or hundreds of thousands of compounds to endlessly screen.


Designing efficiency into any application should be one of the primary principles and only be modified when expanded scope adds additional information. When this simple required element is ignored or modified to adapt to an ever changing landscape of discovery research, the other primary principle that appears to be compromised is value. Value is the true measurement of success. The simplicity of design directly relates to the elegance of its footprint, regardless of its true complexity, an...

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