Abstract

The Application of Flow Technologies to Chemical Biology Research

Nicholas Cosford, Professor, Sanford Burnham Prebys MDI

The interaction of small molecule compounds with specific human proteins, such as enzymes, receptors or ion channels, is one of the fundamental principles upon which the discovery of new medicines is based. Advantages of low molecular weight drugs include the potential for oral bioavailability, efficient tissue (e.g. brain) penetration and low cost of manufacture, among others. The vast majority of low molecular weight drugs are heterocyclic compounds, often comprising several connected heterocyclic rings. This is not surprising considering the propensity of heteroatoms within drug scaffolds to form reversible interactions (electrostatic, H-bonds etc.) within the active sites of proteins, thereby exerting a modulatory effect. Hits obtained from high-throughput screening (HTS) typically exhibit relatively low potency and selectivity for the target protein, in addition to sub-optimal physicochemical (drug-like) properties. Similarly, ligand-based rational design involves the synthesis and testing of compounds in an evolutionary process that leads to new potent and selective analogues. Therefore, the development of new synthetic chemistry methods for the rapid and efficient generation of analogues for in vitro testing is critical for lead optimization. Accordingly, our research encompasses the development of microwave and flow chemistry methods to rapidly access complex, drug-like compounds from readily available precursors. More specifically, we have developed highly efficient methods that combine multiple chemical transformations into single, continuous processes. Further, we are able to demonstrate that these methods can be utilized in the context of medicinal chemistry and chemical biology research to expedite the discovery of new biologically active molecules.