苗头化合物的发现决定了整个药物发现过程的起点,至关重要。苗头化合物的确证阶段如下:
- 排除有潜在反应活性、干扰测试或自聚集的化合物
- 重复活性测试:针对选定的靶标,对高通量筛选得到的活性化合物用相同条件重复测试活性
- 测定量效关系曲线:计算出IC50或EC50值
- 若可获取同系物,进行构效关系(SAR)研究
- 与靶标的结合是否可逆
- 正交测试:用接近于靶标实际生理环境的测试条件或其他不同方法测试苗头化合物的活性
- 二级筛选:生物功能性实验(激动剂/拮抗剂)或细胞实验确证活性
- 评价成药性:使用计算方法预测,或初步测试苗头化合物的物化性质和ADME性质
- 化学上的易处理性:从药物化学家的角度,评价化合物的合成可行性以及在不同化学环境下的稳定性
- 知识产权评价:在特定的数据库检索苗头化合物的专利情况,确保其未被知识产权保护
- 苗头化合物的排序和聚类,初步SAR分析
关于苗头化合物发现的更多信息,笔者推荐阅读这篇ACS的社论(ACS Cent. Sci. 3, 3, 143-147)。以下列出文中部分观点:
- 值得引起注意的是,如果没有采用合适的对照试验,初步筛选得到的苗头化合物中,高达80-100%的化合物是假阳性。
- 从基于有蛋白反应活性PAINS靶标的筛选苗头化合物中也曾发展出不包含PAINS的药物,意识到这一点非常重要。
文中也强调的确证苗头化合物活性的重要性
活性确证实验包括经典的量效关系曲线(dose response curves)、无累积效应(incubation effects)、对温和还原剂的稳定性和对选定靶标的特异性。如果一个分子依据已发表的数据被标记为潜在的PAINS或聚合体,但是能通过这些活性确证实验,说明它可能是一个好的苗头化合物。最后,构效关系(structure-activity relationship, SAR)研究结合系统的机制研究能为苗头化合物的反应特异性提供最令人信服的证据。共价分子和有光学干扰的分子会通过特定的物理机制发挥作用,但这种干扰可以通过对照实验排除。目前,胶体聚集可以通过快速的机械测试和反筛选(counter-screening)来确定。
此外,化合物的结构鉴定和纯度也需要注意,确保重复出的活性是针对同一个化合物。虽然苗头化合物的确证费时费力,但对后续药物发现阶段至关重要。
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