Drug-like hits

It is often quite simple to build desirable physico-chemical properties into MCR-derived libraries. Defining drug-likeness in terms of log P, molecular weight, number of H-bond donors and acceptors, rotatable bonds and polar surface area, molar refractivity, MCR methodologies can produce quality drug-like hits for further optimization. 

In general, there are three milestones for the drug discovery process. The first is the identification of a verified hit series (primary activity in a related series of molecules), the second the determination of a lead series (series with primary activity and drug-like properties), and the third a clinical candidate (activity, positive pharmaceutical, and pharmacokinetic properties devoid of toxicity). An example... 

At the hit triage stage, it is most common to be able to characterize sets of compounds in a kinetic solubility assay. In the assessment and utilization of these data, the potential disconnects between kinetic and thermodynamic solubility must be considered. Low kinetic solubility for a series of compounds should lead a project team to be concerned about the behavior of compounds in biological assays and buffers, as well as the potential for optimizing drug-like properties in that series. Conversely, while high kinetic solubility is a desirable property, chemists should still remain cognizant of the need to assess thermodynamic solubility as compounds are further optimized. 

Fig. 18.3 Variation-based strategies. Left The SHAPES Linking Library [11] consists of drug-like scaffolds connected by linkers that are amenable to combinatorial chemistry (dashed line). Hits are followed up by synthesizing a combinatorial library in which the scaffolds are systematically varied. Center Directed Combinatorial Librari es [12] are comprised of scaffolds containing multiple sites for substituents. Hits are followed up by...

The SHAPES Linking Library was designed to facilitate the use of combinatorial chemistry to follow up screening hits [11]. This library consists primarily of commercially available compounds containing two drug-like scaffolds connected by a linkage that is synthetically accessible. To construct this library, a database of commercially available compounds was filtered to select for drug-likeness and the presence of the desired molecular... 

Partly due to the limited throughput of Caco-2 permeability measurements, the structure-activity evaluation of compounds tested in the hit-to-lead phase is done with minimal permeability information, at best. Given the importance of membrane permeability in drug absorption, early consideration of the permeability characteristics of hit compounds would enhance the drug-like quality, and ultimately the probability of success, of selected lead candidates. To incorporate permeability information into the hit-to-lead phase of the drug discovery process it is necessary that permeability measurements be made quickly and with small amounts of material. Thus, efforts have been made to automate and miniaturize the Caco-2 permeability assay. 

---