Fragment growing

ICgo = 790 pM (M6P-C125 ELISA assay) LE = 0.39 koal/mol/atom 

LE = 0.43 kcal/mol/atom LE = 0.48 kcal/mol/atom 15 heavy atoms 5 heavy atoms 

Moreover, even when two individual fragments can be identified, it can be difficult to properly link them. This was illustrated by one of the earliest Abbott papers in which changing the hnker length by just one methylene reduced the affinity by as much as 100-fold [75]. Even subtle chemical changes in the linker can have profound effects on binding. In one example, changing an oxime moiety to an amine (or vice versa) reduced affinity by one to two orders of magnitude [80]. 

Overlaying the structures of the adenine-pocket binding fragments with the substrate-pocket binding fragments revealed that they were separated by about 

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When a fragment grows to KXX) km, it can capture the residual gas in the nebula, and this is the main process of growth together with the rare collisions with residual planetesimals. 

Section 1 discussed, somewhat theoretically, fragment linking and fragment growing, and acknowledged that these are but two ends of a continuum. The examples below demonstrate how these simple categories apply in practice, as well as how they break down. 

Edink E et al (2011) Fragment growing induces conformational changes in acetylcholinebinding protein a structural and thermodynamic analysis. J Am Chem Soc 133(14) 5363-5371... 

CiuDi, A., Blundell, T.L, and Abell, C. (2009). plication of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. An mmdte Chemie, International Edition, 48,8452-8456. 

Scheme 6.9 Fragment growing to discover MCL-1 inhibitors at AbbVie.

Fig. 63. Method used for permanent cultures in vivo. Stem line fragments grow but remain undifferentiated test fragments pass metamorphosis and develop into adult structures. (After Hadorn, 1965)...

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