新型PHD抑制剂类口服抗贫血药物分子的计算机辅助设计

Computer Aided Design of New PHD Inhibitors for Oral Anti-Anemia Drug Molecules

摘要: 目的：以目标靶蛋白为研究对象设计一系列可口服的抗贫血类化学药物分子结构。方法：本文针对肾性和肿瘤相关性贫血设计口服小分子治疗药物。贫血，特别是糖尿病性贫血治疗领域是一个非常有前景的市场。HIF-PHD抑制剂作为新型治疗贫血药物，可从注射用促红细胞生成药物, 尤其是透析前慢性肾病患者中获取较大的市场份额。更重要的是，由于这类药物可作为对现有促红细胞生成药物治疗无效或因故不能使用、或因价格太贵而未使用人群的一种新的、有效的替代治疗选择，故也具显著拓展贫血治疗市场规模的潜力。通过对已知有活性的化合物的结构特性以及与靶蛋白的作用机制为基础进行研究，设计合成出治疗效果更好的、副作用更小的潜在治疗贫血的口服药物，在贫血治疗领域必将占有一席之地。采用计算机辅助药物设计将理论计算和实际试验相结合，通过计算机的模拟、计算和预算药物与受体生物大分子之间的关系，设计和优化脯氨酸羟化酶抑制剂类先导化合物。采用体外模拟试验进行理论验证，以期对发现新的具有更大的潜在活性药物提供较大的应用价值。结果：设计出一系列以吲哚为母核结构的化合物分子，通过分子对接从理论上证实其中一些分子化合物为潜在的活性化合物。结论：为新型口服抗贫血化学药物的开发奠定了一定的理论基础。

Abstract: A series of small molecule compound structures oral administration anti-anemia drugs were de-signed based on target protein. Small molecule drug designed in this project is targeted at renal and cancer related anemia. Anemia treatment field, especially diabetic anemia, is a very promising market. As a new kind of anemia inhibitor, HIF-PHD inhibitors could obtain a larger market share from erythropoietic drugs for injection, especially pre-dialysis patients with chronic kidney diseases. More importantly, this kind of drugs could be used as a new, effective replacement therapy for those patients that could not be treated by the existing erythropoietic drugs for that the drugs are invalid for them, or cannot be used for them for some other reasons, or too expensive for them to afford to. So, the potential drugs with better therapeutic effects, less adverse effects, and oral administration developed on the basis of structural characteristic of known active compound and its mechanism of action with target proteins, are doomed to hold a place in the field of anemia treatment. By com-bining theoretical calculation and practical test together via computer aided drug design, with the computer’s simulation, calculation and estimation on the relationship between drugs and biological receptor molecules, this project starts from designing and optimizing the leading compounds of proline hydroxylase inhibitors, then carrying out In Vitro experiments to verify the theoretical ac-tivity, which is of great application value for discovering greater potential active agents. Result: A series of compounds with indole as the parent nucleus structure were designed and some molecular compounds were theoretically confirmed by molecular docking as potential reactive compounds. Conclusion: It has laid a theoretical foundation for the development of new oral anti-anemia drugs.