Large and flexible compounds are of interest in pharmaceutical programs aimed at challenging protein targets that cannot be modulated by Rule of Five (Ro5)-compliant small molecules. Given their particular structural features, early drug discovery is now in charge of identifying which molecular descriptors should be used in the often called beyond-Rule-of-5 (bRo5) chemical space. Here, we focus on flexibility descriptors. First, we discuss the concept of flexibility and then focus on the number of rotatable bonds (NRot), the most common in silico descriptor. After identifying the pros and cons of NRot, we discuss how Kier's index Φ can replace NRot, and the limits of 3D descriptors. Finally, we show how a misuse of NRot and Φ can result in incorrect interpretations of the impact of flexibility in the bRo5 space and how flexibility has potential in the prospective design of orally bioavailable bRo5 drug candidates.

中文翻译：

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早期药物发现的灵活性：专注于5规则以外的化学领域。

大型灵活的化合物在针对具有挑战性的蛋白质靶标的药物程序中颇受关注，这些蛋白质靶标不能通过遵循五规则（Ro5）的小分子进行调节。鉴于其特殊的结构特征，现在的早期药物开发是负责确定在通常被称为5规则以外（bRo5）的化学空间中应使用哪些分子描述符。在这里，我们专注于灵活性描述符。首先，我们讨论灵活性的概念，然后关注可旋转键的数量（NRot），这是最常见的计算机描述符。在确定了NRot的优缺点之后，我们讨论了Kier索引Φ可以如何代替NRot，以及3D描述符的限制。最后，