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Compound Design by Fragment‐Linking
Author(s) -
Ichihara Osamu,
Barker John,
Law Richard J.,
Whittaker Mark
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201000174
Subject(s) - fragment (logic) , linker , fragment molecular orbital , superadditivity , affinities , chemistry , stereochemistry , computational biology , computer science , molecule , algorithm , biology , mathematics , molecular orbital , organic chemistry , mathematical economics , operating system
The linking together of two fragment compounds that bind to distinct protein sub‐sites can lead to a superadditivity of binding affinities, in which the binding free energy of the linked fragments exceeds the simple sum of the binding energies of individual fragments (linking coefficient E <1). However, a review of the literature shows that such events are relatively rare and, in the majority of the cases, linking coefficients are far from optimal being much greater than 1. It is critical to design a linker that does not disturb the original binding poses of each fragment in order to achieve successful linking. However, such an ideal linker is often difficult to design and even more difficult to actually synthesize. We suggest that the chance of achieving successful fragment linking can be significantly improved by choosing a fragment pair that consists of one fragment that binds by strong H‐bonds (or non‐classical equivalents) and a second fragment that is more tolerant of changes in binding mode (hydrophobic or vdW binders). We also propose that the fragment molecular orbital (FMO) calculations can be used to analyse the nature of the binding interactions of the fragment hits for the selection of fragments for evolution, merging and linking in order to optimize the chance of success.