Capter 11 Filtering in Drug Discovery

This chapter discusses the concept of filtering in drug discovery. Multiple filters may be incorporated into a definition of drug-likeness and this leads to tradeoffs among compound properties in compounds intended for screening. The optimization of compound properties may require some type of multiparameter optimization scheme in library design. Fingerprint algorithms can be used to guide diversity. Filters also need to be employed in the chemistry synthesis planning process so that good quality compounds are made. Differences in property ranges between oral and injectable drugs are summarized in the chapter. Oral drugs are lower in MWT and have fewer H-bond donors, acceptors, and rotatable bonds. A scheme for separating central nervous system (CNS)- from non-CNS-active drugs in the WDI allowed the discovery of simple parameters relating to passive blood brain barrier (BBB) permeability and the prediction of p-glycoprotein (PGP) affinity. The PGP transporter is a major barrier to the entry of compounds to the CNS. Appropriately determined PGP efflux ratios can be used as a measure of compound affinity to PGP.