Challenges of Aufheben to Promote Druglikeness: Chemical Modification Strategies to Improve Aqueous Solubility and Permeability

A key challenge in drug discovery is to endow candidate bioactive molecules with druglike properties. However, the optimization of critical, often-conflicting physicochemical properties through chemical modifications is particularly difficult, and the term Aufheben has been adopted to describe the simultaneous preservation and modification of apparent opposites to achieve improvement. This perspective examines strategies to reconcile conflicting parameters, such as lipophilicity/hydrophilicity, druglikeness/flatness, and druglikeness/molecular weight, in order to improve the aqueous solubility and membrane permeability of drug candidates. We review and categorize numerous molecular design strategies that have been investigated to address these challenges and highlight some recent successful examples.