Molecular chameleons adaptability in target binding.

Estimates show that up to 85% of the human therapeutic proteomes are undruggable by traditional small molecules. Macrocycles, a class of molecular leads, often extend beyond the traditional drug space and offer the potential to modulate challenging targets within this 85%. These modalities exhibit significant conformational flexibility and often function as molecular chameleons, enabling them to adapt to environments with varying polarities while ensuring good oral bioavailability. In this study, we explore the conformational adaptability in target binding of the three known molecular chameleons, paritaprevir, grazoprevir, and simeprevir, by docking their experimental crystal structures, solution conformations, and target-bound structures into multiple protein targets, including human drug transporters associated with drug-drug interactions and COVID-19 related proteins. Our findings reveal that the macrocyclic core conformational class, or "chameleonic group," determines the overall pharmacophore conformations and influences the conformational changes required for binding to various proteins. These insights provide a pathway toward rationalizing drug optimizations for molecular chameleons as well as offering specific guidance for improving Hepatitis C virus nonstructural protein 3/4A inhibitors, including providing a starting point for their COVID-19 repurposing and cancer therapy.