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...