Designing Effective Screening Libraries
Shrewd selection of screening compounds is one of the most vital enabling steps in the drug discovery process. A screening library must have the correct balance of properties such as molecular weight and lipophilicity. An ideal hit molecule must also be amenable to chemical elaboration, show reasonable levels of cell permeability, and have a range of commercially available analogues, some of which have also been tested in the same assay.
We are also interested in experimental studies such as ALARM NMR and PAINS which have identified molecular scaffolds that form the basis for promiscuous inhibitors and thus yield false positives in many screening assays. We work on development of small molecule screening libraries specifically targeted towards PPIs. Recent analysis collected in the TIMBAL database suggests that inhibitors of PPIs have different properties than inhibitors of buried binding sites.
We are interested in the general applicability of this finding and in understanding the difference between “traditional” inhibitors of buried binding sites and inhibitors of PPIs.