Tools for fragment based drug discovery

Ligandibility Studies

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LIGANDIBILITY STUDIES


We and others (e.g. Hajduk, J. Med. Chem., 2005; Edfeldt, Drug Disc. Today, 2011) have noted a strong correlation between the hit rate (and hit diversity) in NMR fragment screening and the ligandability of a target. (Ligandability is often refered to as druggability, which includes more criteria other than ligand-target binding). ZoBio has developed its own correlation between TINS and ligandability as shown below.

In TINS, binding is best represented by the ratio of the heights of each peak of a compound in the presence of the reference and the target (the T/R ratio). Each of these graphs presents the number of compounds with a T/R in each of the bins presented on the x-axis. This gives a profile of the screen that is unique for each target. The figure below demonstrates how the profile varies with the known ligandibility of three different targets.

Ligandability

In the image below, the TINS profiles of four membrane targets are overlayed. The class II receptor (Y, blue) is evidently less ligandable than either of the class I receptors, as indicated by the narrower profile. The ligandability of the ligand gated ion channel (LGIC, X, green) is only moderately better, while the profiles of both α2AR (red) and β2AR (black) are consistent with their known ligandability. These data extends the concept of ligandability to membrane proteins for the first time.

TINS_profiles


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