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...

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Diversity Series, Part 3

February 27, 2017

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