Drug discovery based on the structure of FKBP12:Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

摘要

By choosing neuroimmunophilin FKBP12 as a therapeutical target, we have attempted to discover a new structural drug for treating neurodegenerative disease. This drug should possess neurotrophic activity and not affect the immune system. Based on the crystal structure of FKBP12, FK506 and Cal-cineurin complex, a series of small organic molecules were designed. These molecules were to have the ability of binding to FKBP12 in a virtual screening. By using a solution parallel synthetic method, these compounds were synthesized. The neuroprotective and neuroregenerative activities of these compounds were evaluated by binding assays, PC12 cells survival and neurite outgrowth model, chick dorsal root ganglion cultures (DRG) and 6-OHDA lesioned mice sympathetic nerve endings model. The evaluation results of these compounds showed that compound N308 has great promise as a candidate for a neuroprotective and neuroregenerative agent.