Fragments to Find Hot Spots in Binding Pockets

Given that for slope of the size versus affinity relationships are very consistent (AMW = 64 18 per log unit of affinity increase p-Kd) the maximal affinity for a given optimized fragment could be predicted [74], Alternatively, the binding efficiency index [38] (BE = (pJfd/MW)) should remain constant throughout a fragment and lead optimization campaign. 

A range of computational approaches to identify and rank protein binding site hot spots have also been developed to predict binding site hot spots. However, the scope of this chapter does not allow for this to be discussed in detail. The reader is referred to reviews on the topic [76,77]. 

Nonclassical Hydrogen Bonds - Interactions of Halogen Atoms with Il-Systems and Carbonyl Groups Factor Xa and Cathepsin L 

The constructive impact on binding and the geometric dependency of this type of bond can be clearly observed by a systematic study investigating the impact of binding of differentially substituted ligands to cathepsin L [80]. 

S3 pocket binding group and short halogen bond, 3.08 A [80]. (PDB Codes 

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