Target-based drug discovery: from protein structure to small-molecules by MCR chemistry

Target-based drug discovery normally starts with the identification and validation of a drug target which can be used for lead screening. The vast majority of the approved drugs use proteins as their targets. Once the target protein was identified, the lead compounds can be obtained by high throughtput screening or fragment based drug discovery. Isocyanide-based multicomponent reactions (IMCR) are by far the most versatile reactions that can construct relatively complex molecules by one-pot synthesis. More importantly, the development of post IMCR modifications significantly improves the scaffold’s diversity. In this thesis, we established a systematic protein refolding method to evaluate the impact of the “helper” molecules, the pH, buffer system and time on the protein refolding process in a high-throughput fashion. In the chemistry part, we describe the fast and efficient synthesis of aminotetrazolopyrazinone derivatives, isoquinoline derivatives, benzo[d]azepinone scaffolds, thienopyridine scaffolds and tetrazole fused heterocycles by Ugi post-cyclization strategy. In addition, a library of positional isomeric 1H-tetrazoles and 5H-tetrazoles for the purpose of testing binding hypothesis of isomeric tetrazoles in fragment-based drug discovery was also described.