What is a high-quality lead compound

Potency alone is a poor predictor of lead quality ligand efficiency 

Most componnds medicinal chemists work with have between 20 and 50 non-hydrogen atoms, and their ligand efficiency falls far below the theoretical limit of -1.5 kcal/ mol per non-hydrogen atom. It is instructive to analyze why this might be the case. 

One reason is pnrely sterical and is related to the 3D strnctnre of a molecule itself. As the size of the molecule grows, more and more atoms get buried in the bulk of the molecule and are not exposed to its surface. They are thus unable to interact with the receptor and cannot contribute to binding energy. 

Designing lead-like libraries for biochemical screening 

There is another reason to favor smaller molecules. Screening a library is an experiment in which chemical space is sampled with regard to the ability to bind to the target of interest. The better a given library samples chemical space, the higher the probability of finding aU possible 

---