Virtual fragment linking

Crisman TJ, Bender A, Milik M et al (2008) Virtual fragment linking an approach to identify potent binders from low affinity fragment hits. J Med Chem 51 2481-2491... 

A similar virtual fragment linking approach validated across a variety of different target classes has also been reported [88]. A combination of virtual and experimental (NMR, biochemical) screening methods was employed to identify novel scaffolds for the design of kinase-targeted libraries [89]. 

Crisman, T.J., Bender, A., Milik, M., Jenkins, J.L., Scheiber, J., Sukuru, S.C., Fejzo, J., Hommel, U., Davies, J.W, and Click, M. (2008) Virtual fragment linking an approach to identify potent binders from low affinity fragment hits. Journal of Medicinal Chemistry, 51, 2481-2491. 

In addition, alternate virtual screening methods can incorporate activity-class-characteristic features. For example, by counting the number of activity-characteristic features in test compounds, active molecules were identified that possessed new combinations of activity-characteristic features that were not observed in reference compounds, resulting in chemotypes that were distinct from any of the reference compounds [13]. Similarly, virtual fragment linking [7] used features enriched... 

Figure 7.7 Combinatorial molecule assembly scheme. Resultant candidate molecules are objects that have building-blocks attached to scaffolds via linkers. Three user-definable fragment sets are needed to feed the algorithm with fragments for each domain. A few example fragments of each type are shown for clarity. For virtual library enumeration, each database fragment gets linked to each other fragment following a combinatorial assembly scheme.

As is seen, the values are well described by the above function with the parameters E = 34.7 kj-mol" and log x = -14.2. It was assumed that the aminoxyl fragment participates in a sufficiently rapid cooperative motion involving the aminoxyl group and several carbon atoms of the main chain linked to this group. This additional mobility produces additional averaging of A and g-tensors to virtually an isotropic level. For this reason, the correlation times estimated in the considered system are close to the x values for the rotation of spin probes determined by the motion of molecular segments. 

---