Hydroxyl Groups in Synthetic and Natural-Product-Derived Therapeutics: A Perspective on a Common Functional Group.

By forming extended hydrogen-bond networks, the contribution of hydroxyl groups to affinity can reach several orders of magnitude. However, because of the high directionality of their interactions, a maximal affinity gain can only be achieved when the ligand scaffold allows a perfect spatial fit with the binding site. In contrast to the broad potential of hydroxyl groups for molecular recognition is their exceptionally high desolvation penalty, which can equally reduce binding affinity. As a consequence, alcohols are rarely present in synthetic drugs but predominantly found in therapeutics derived directly or inspired from natural products, which were shaped under evolutionary pressure. In this perspective, advantages as well as drawbacks influencing the use of OH groups in medicinal chemistry are discussed and illustrated with four exemplary case studies. Additionally, guidelines for drug design are derived from common features found in existing therapeutics.