1.9 Lipinski and Hydrogen-Bonds

The work of Lipinski [1] introduced the application of simple filter-like rules to roughly predict late-stage PK properties, in particular oral bioavailability. Unfortunately, Lipinski's "Rule-of-Five" has come into the common vernacular to such a large degree that some of the specific details are often lost in the commotion. There are two critical examples of this. First, Lipinski used "violation of 2 rules" to categorize compounds. In the subsequent analysis, a significant difference in the two populations of molecules was detected, however, little analysis of the importance of a single violation was done. However, many now consider a single violation to be bad and two violations to be worse. At this writing, we don't know of evidence to support this. Second, Lipinski used well-codified and well-understood yet imprecise definitions of "hydrogen-bond donors" and "hydrogen-bond acceptors" in his classification model. While this makes the algorithm quite understandable and easy to implement, it sometimes causes confusion with those who prefer more refined definitions of hydrogen-bond donors and acceptors.

To address the first problem, Filter allows users to set the number of Lipinski failures required to reject a model. In keeping with the original publication, the default value is 2. To address the second problem, Filter calculated two kinds of hydrogen-bond donors and acceptors. In the Lipinski calculation, the published definitions are used (donor count is the number nitrogen or oxygen atoms with at least one hydrogen attached and acceptors are the number of nitrogens and oxygens). For calculation of the number of donors and acceptors in the molecule for the sake of chemical properties, a more complex algorithmic approach is taken. This approach identifies the donors and acceptors outlined in the work of Mills and Dean [13] and also in the book by Jeffrey [14].

				FILTER Database preparation Property calculation

				FILTER Database preparation Property calculation