大片专利到期以及越来越严格的批准规定，迫使制药行业寻求和开发有效的药物发现技术。在过去的几十年中，计算算法和计算机处理能力的进步使基于结构的虚拟筛选成为早期药物发现和开发中的流行工具。使用计算技术能够识别潜在候选药物大大减少化学合成和体外测试所需的时间和成本。同时，寻找现有药物的新用途已经成为补充研发管线的战略。开发现有药物新适应症的方法称为药物重新定位。
过去二十年药物研发的主流范式主要是基于靶标的药物发现。在该过程中，将候选化合物与分离的生物分子进行筛选，以鉴定对具体疾病靶标具有高效力和选择性的分子靶向药物。然而，从这些努力获得的结果达不到预期，由于不期望的药代动力学或药物代谢而频繁地出现后期临床失败。
药物重新定位背后的概念是基于小分子的混杂性质以及细胞信号传导网络和信号转导途径的相互联系。由于活体内含有大量不同的化学和生化实体，实际上小分子不可能达到100％的同源选择性。虽然这种“交叉”在传统药物开发过程中被认为是不利的，但越来越多的证据表明，某些批准的药物可能发挥多种药理作用，与其预期适应症几乎没有明确的联系。这可以解释同一生物分子靶标开发的药物之间观察到的差异功效和副作用。
将新药推向市场相关的成本上涨和困难上升使得药物重新定位技术进一步发展。近年来越来越严格的审批条例进一步增加了将新药推向市场所需的资源投入。在这种情况下，由于在以前的临床试验中已经获得的现有药物的药代动力学和毒理学数据的可用性，药物重新定位可以显著减少与新发现相比的开发时间和成本。因此，药物重新定位可以显著降低与临床相关的风险。
近年来，已经结合药物重新定位研究了各种各样的技术，试图加速或简化药物研究的早期阶段，如表型筛选，高通量实验筛选和数据库挖掘，这些策略旨在发现潜在的候选药物。
应该强调的是，虽然药物重新定位节约了时间和成本，但并不能保证顺利进入市场。可能需要进一步的结构修饰以增强对新靶标的特异性，同时选择性地减少对原始靶标的活性。此外，虽然候选药物的药代动力学、药效学和毒理学数据的可用性允许化合物绕过常规的初步筛选测定，但重新定位药物的剂量和功效仍然须在合适的动物疾病模型中进行严格测试以用于次要适应症。
药物重新定位有时可能会遇到专利相关问题。药物开发的昂贵而艰巨的性质迫使制药公司采取广泛措施保证投资回报。然而，这种保护政策可能会阻碍重新定位药物商业化。在重新定位过程中，也应该仔细考虑市场份额、知识产权和重新定位药物新发展规划的其他重要方面。
基于结构的虚拟筛选
基于结构的虚拟筛选允许以快速和成本有效的方式评估大型化合物库和生物分子靶标之间的相互作用。除了计算筛选之外，还可以使用分子对接来研究小分子与靶点结合位点的结合模式。
基于结构的虚拟筛选和药物重新定位的结合代表了新药物开发的高效方法。现有药物是一类生物利用度和相容性被验证的结构，故通过虚拟筛选发现的高效命中化合物在细胞或动物研究中失败的可能性会降低。此外，虚拟筛选使得学术团体或小公司不需要购买数千种化合物，能够对现有药物进行探索性重新定位，对抗新的疾病靶标。
基于分子对接的药物重新定位可以通过“单一靶标”方法进行操作，该方法旨在鉴定候选药物与特定靶标之间的潜在相互作用。 或者，“反向对接”可用于研究现有药物与已知治疗靶标的结合。这种方法用于揭示新的药物-靶相互作用以及评估药物化合物对所需靶标的选择性。 此外，计算机技术可用于预测优化药物类似物的吸收、分布、代谢、排泄和毒性（ADMET）特征。
研究案例
重新定位药物作为蛋白-蛋白相互作用调节剂
肿瘤坏死因子-α（TNF-α）是通过调节多种信号通路参与炎症反应的重要人细胞因子。 TNF-α细胞水平的差异已经涉及多种炎症性疾病。临床改进的生物制药英夫利昔单抗靶向TNF-α。然而，使用TNF-α抗体可能会引起自身免疫抗体反应或削弱机体免疫系统。这激发了通过基于结构的虚拟筛选和实验筛选鉴定几种TNF-α三聚体小分子抑制剂的发展。2011年，Ma, Leung和同事采用基于结构的高通量虚拟筛选方法，从上市药物库中鉴定TNF-α的小分子抑制剂。目视检查高评分结构，挑选7个化合物进行TNF-α抑制实验测试。随后证实这些化合物在体外破坏TNF-α-TNF-α受体相互作用，并下调人细胞中TNF-α驱动的基因表达。
达芬那新（Darifenacin）通过拮抗毒蕈碱乙酰胆碱受体（mAChRs）来治疗膀胱过度活动症（OAB）综合征，而依泽替米贝是肠道中胆固醇的有效抑制剂，通常与他汀类药物合用控制胆固醇水平。
分子对接结合模式图
参考资料
1. Ma D L, Chan D S H, Leung C H. Drug repositioning by structure-based virtual screening[J]. Chemical Society Reviews, 2013, 42(5): 2130-2141.
2. Nosengo N. Can you teach old drugs new tricks?[J]. Nature, 2016, 534(7607): 314-316.
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