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...
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...
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...
Zenobia Therapeutics was founded in 2008 by Drs Vicki Nienaber and Robert Meadows. Zenobia’s founders are pioneers in the field of fragment-based lead discovery (FBLD) contributing to the model NMR screening paradigm, SARbyNMR (1,2) and inventing the first crystallographic screening method, CrystaLead (3).
Recognizing that diseases of the CNS are a significant unmet medical need, Zenobia Therapeutics quickly adapted the strengths of FBLD to address one of the biggest challenges of CNS drug discovery: finding leads that cross the blood-brain-barrier (BBB). The leading chemical properties for brain penetration include low molecular weight and clogP. So starting with small simple fragments and growing them systematically into small efficient leads seemed a strategic advantage in discovery of a CNS-directed therapeutic (4). Furthermore, data mining of historic clinical data showed that small simple compounds have a better chance of success in the clinic. This coined the phrase: “Start sm...