Flexibility in early drug discovery: focus on the beyond-Rule-of-5 chemical space

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.