Developing small molecules for chemical genetics European chemists made significant advancements in the field of chemical genetics by generating molecules diverse enough for screening. Health © Shutterstock Chemical genetics refers to the study of biological systems through the intervention of small molecules to alter the way proteins work. An important tool for chemical genetics is a collection or 'library' of small compounds used for the chemical screen. This can be applied to a known phenotype in order to identify the protein responsible (forward genetics) or to a specific protein and observe the resultant phenotype (reverse genetics). In order to exploit the advantages of the small molecule approach of chemical genetics advances must be made in finding selective small molecules to any protein quickly, cheaply and with adequate selectivity. With this in mind, the EU initiative 'A new strategy for the diversity-oriented synthesis of skeletally diverse alkaloid-like compounds for chemical genetic studies' (Multiscaffold) aimed to develop a novel strategy for generating skeletally diverse alkaloid-like compounds. Project partners dealt with the challenging process of diversity-oriented synthesis (DOS) which represents the synthesis of relatively small libraries of organic molecules that are structurally more complex. They also have a greater variety of core structures than those produced by traditional combinatorial chemistry. The approach followed to achieve this involved the development of a mutli-component reaction that generated 10 polycyclic scaffolds. Chemists investigated the potential of these scaffolds to be transformed into alternative structures, in other words to be able to 'switch' from one scaffold to the next. The resultant library of approximately 100 alkaloid-like small molecules was highly diverse offering combinatorial variation among scaffolds. The main achievements of the Multiscaffold project offer significant insight into the DOS process. Application of the small molecule library in cell- and protein-based genetic screens is expected to aid the identification of molecules that may be developed as drugs.
