The use of bioisosteres in drug design is usually applied to improve activity through more favourable conformation or electronics, improve ‘bad’ pharmacokinetics (PK), or eliminate metabolic pathways. These modifications are often guided by the intuition of the medicinal chemist – ‘trial and error’. Traditional replacements such as ester to amide, or heterocyclic replacement may be employed without truly understanding the resultant changes in electrostatics and shape [1]. Frustratingly, some structures are particularly irreplaceable, and literature precedent is incredibly sparse.
The quinone moiety is infamous for its persistent use in small molecule medicinal chemistry, especially in screening libraries, despite its PAINS status and metabolic liability. This may result in off-target activity, or toxicity [2]. Despite this, it remains one of the most frequently incorporated functionalities touted as a privileged scaffold [3]. Common methods of bioisosteric replacement are often not-suitable resulting in poorer activity or PK characteristics.
Herein we describe a high-level, but cost-effective DFT method for the elucidation of key electronic and structural characteristics in quinones, and their subsequent replacement with non-quinone bioisosteres. This approach provides both quantitative and qualitative pharmacophoric information which allows for the comparison across both traditional and non-traditional bioisosteres. This was ultimately employed to remove a key quinone functionality in an inhibitor of the endocytic protein clathrin through a series of modifications, retaining activity.