Ligand efficiency and molecular size

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Molecular complexity models of ligand binding typically predict that ligand efficiency (LE) will decrease during the process of elaborating a fragment hit. This is the basis of the fit quality (FQ) metric that Mel reviewed in her last post. It’s interesting to take a look at a 2006 article which actually pre-dates the FQ articles. This study attempted to track LE through the lead optimisation process for 18 drug leads from 15 different projects. The main conclusion of the study was that ‘a nearly linear relationship exists between molecular weight and binding affinity over the entire range of sizes and potencies represented in the dataset’. In other words, LE changed little during the optimisation process for these leads.

Comments anyone?

Literature cited:
Hajduk, Fragment-Based Drug Design: How Big Is Too Big? J. Med. Chem. 2006, 49, 6972-6976 DOI