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 weight. So high molecular weight fragments have much less room to grow into a clinical candidate with a high probability of success.
In this Guideline of Two (GoT Frags), molecular weight is kept low, ideally < 200 to yield a final candidate < 350-400, the statistical "sweet spot" for marketed products.
Low molecular weight compounds are statistically more likely to succeed in the clinic and "starting small and staying small" is a viable strategy in drug discovery.
Guideline 2: cLogP ≤ 2
High cLogP compounds tend to fall out as clinical trials progress and have been shown to lead to a higher incidence of toxicity. Like molecular weight, cLogP also tends to increase during lead optimization. This is another parameter that is closely monitored in assembly of our library.
As lipophilicity is often added during fragment optimization, we believe the ideal starting cLogP is < 1-2. The majority of our library meets these criteria.
Low cLogP is a predictor of success in the clinic and figures heavily in the design of our libraries and during the fragment-to-lead stage
Guideline 3: H-bond donors ≤ 2
Hydrogen bonding (H-bonding) is a significant influence on the permeability (how easily a drug crosses either the intestinal membrane or blood brain barrier) of a drug. Though it was initially believed that hydrogen bond donors and acceptors are of equal importance in helping to determine a drug's permeability, it has been found that hydrogen bond donors are more predictive.
To increase cell permeability, in particular for the CNS, this parameter should be kept low. For fragment hits with a high number of h-bond donors (>2), this parameter should be monitored closely during fragment-to-lead.
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-Wenlock, M. C., Austin, R. P., Barton, P., Davis, A. M., & Leeson, P. D. (2003). A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs. J. Med. Chem. Journal of Medicinal Chemistry, 46(7), 1250-1256. doi:10.1021/jm021053p
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