The Role of Allylic Strain for Conformational Control in Medicinal Chemistry

Itis axiomatic in medicinal chemistry that optimization of thepotency of a small molecule at a macromolecular target requires complementaritybetween the ligand and target. In order to minimize the conformationalpenalty on binding, both enthalpically and entropically, it is thereforepreferred to have the ligand preorganized in the bound conformation.In this Perspective, we highlight the role of allylic strain in controllingconformational preferences. Allylic strain was originally describedfor carbon-based allylic systems, but the same principles apply toother types of structure with sp(2) or pseudo-sp(2) arrangements. These systems include benzylic (including heteroarylmethyl) positions, amides, N-aryl groups, aryl ethers,and nucleotides. We have derived torsion profiles from small moleculeX-ray structures for these systems. Through multiple examples, weshow how these effects have been applied in drug discovery and howthey can be used prospectively to influence conformation in the designprocess.

Automated summary

It is well-known in medicinal chemistry that optimizing the potency of a small molecule at a macromolecular target requires compatibility between the ligand and target. This study focuses on the role of allylic strain in controlling conformational preferences. We examine various systems, such as benzylic positions, amides, N-aryl groups, aryl ethers, and nucleotides, and demonstrate how allylic strain has been utilized in drug discovery and can be prospectively used in the design process to influence conformation.