Further development of our Drug Discovery Platform FORECASTER and its application to the design, synthesis and biological evaluation of prolyl oligopeptidase Inhibitors

抑制脯氨酰寡肽酶(POP)是治疗阿尔茨海默病的一种非常有前途的策略，POP抑制剂是有待开发的候选药物。Moitessier和他的同事最近报告了一种有效的、精准的、高度选择性的POP抑制剂。然而，其稳定性和药动学特征仍需改进。由于不良的药代动力学特征，大量药物发现和开发项目在开发后期失败。在药物发现过程的早期整合对潜在候选药物的吸收、分布、代谢、排泄和毒性(ADME-Tox)的评估有望显著降低失败率。在这种情况下，使用计算方法预测ADME-Tox谱被视为一种高通量和廉价的选择，可以补充体外或体内的中低通量分析。Moitessier和他的同事开发了一个复杂的程序平台(Forecster)，可以执行虚拟筛选、对接等操作(www.fitted.ca)。在这项研究中，我们计划结合我们在有机合成、药物化学、代谢和软件开发方面的互补专业知识，1.开发准确的电子计算方法来预测细胞色素P450介导的代谢和P450抑制，并在我们的平台预测器中实施；2.将这套程序应用于改进的POP抑制剂的开发。

Prolyl Oligopeptidase (POP) inhibition is a highly promising strategy for the treatment of Alzheimer's disease and POP inhibitors as drug candidates are to be developed. Moitessier and co-workers have recently reported a potent, permeant and highly selective POP inhibitor. However, its stability and pharmacokinetic profile need to be improved. A large number of drug discovery and development projects fail at the late development stages due to poor pharmacokinetic profiles. Integrating the evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) of potential candidate drugs early in the drug discovery process is expected to significantly reduce this failure rate. IIi this context, predicting the ADME-Tox profile using computational methods has been seen as a high-throughput and inexpensive option that could complement low to medium throughput in vitro or in vivo assays. Moitessier and co-workers have developed a sophisticated platform of programs (FORECASTER) which performs virtual screening, docking and more (www.fitted.ca). In this research, we plan to combine our complementary expertise in organic synthesis, medicinal chemistry, metabolism and software development to 1. develop accurate in silico methods that predict the cytochrome P450-mediated metabolism and P450 inhibition and implement them in our platform FORECASTER; 2. apply this suite of programs to the development of improved POP inhibitors.