Computational approaches for small-molecule drug discovery now regularly scale to consideration of libraries containing billions of candidate small molecules. One promising approach to increased speed in evaluating billion-molecule libraries is to develop succinct representations of each molecule that enable rapid identification of molecules with similar properties. Molecular fingerprints are thought to provide a mechanism for producing such representations. Here, we explore the utility of commonly-used fingerprints in the context of predicting similar molecular activity. We show that fingerprint similarity provides little discriminative power between active and inactive molecules for a target protein based on a known active. We also demonstrate that, even when limited to only active molecules, fingerprint similarity values do not correlate with compound potency. In sum, these results highlight the need for a new wave of molecular representations that will improve the capacity to detect biologically active molecules based on similarity to other such molecules.

中文翻译：

---

分子指纹在寻找多种活性药物时有用吗？（不）

小分子药物发现的计算方法现在定期扩展以考虑包含数十亿候选小分子的库。提高评估十亿分子库速度的一种有前途的方法是开发每个分子的简洁表示，从而能够快速识别具有相似特性的分子。分子指纹被认为提供了产生这种表征的机制。在这里，我们探讨了常用指纹在预测相似分子活性方面的实用性。我们表明，对于基于已知活性的目标蛋白，指纹相似性在活性分子和非活性分子之间几乎没有提供区分能力。我们还证明，即使仅限于活性分子，指纹相似性值也与化合物效力无关。总之，这些结果凸显了对新一波分子表征的需求，这将提高基于与其他此类分子的相似性检测生物活性分子的能力。