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...
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...