Designing a Fragment Process to Fit Your Needs - Fragment-Based Drug Discovery - page 14

2
Designing a Fragment Process
to Fit Your Needs
Edward R. Zartler and Michael J. Shapiro
2.1 Fragment Definition
While the definition of a fragment is in the eye of the beholder, it is always considered a
molecule of lower molecular weight than its corresponding drug. [ 1 ] Typically, fragments
have molecular weights of 100-250 Da (7-20 heavy atoms), have less functionality than
the daughter molecule and 'low' binding affinity. Typical binding affinities for fragments
range frommM to low M; although nanomolar fragment sized molecules do exist. A 'rule
of three' for fragments has been prescribed for 'good fragments', [ 2 ] comparable to the 'rule
of five'for drug-like compounds. [ 3 ] Fragments occupy a small region of total chemical space
due to their low complexity, but reasonably sized libraries (several thousands) can theor-
etically explore a great majority of fragment space, whereas 'lead-like' molecules cannot
possibly explore all of the 10 60 possible molecules that exist in chemical space [ 4 ] or even a
significant fraction of them. The diversity of a fragment library is encompassed in a smaller
number of compounds than it would be for a diverse high-throughput screening library
of lead-like compounds. The simple nature of fragments may even prove advantageous in
a screening setting as fewer detrimental effects of 'nonfunctional' molecular appendages
'bump' into the protein surface. [ 5 ]
2.1.1 Overview of the Design Process
The design of a robust fragment-based drug discovery (FBDD) process can lead to large
increases in productivity in lead generation and lead optimization. [ 6 ] It should be noted that