Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation

Macrocycles play an increasing role in drug discovery but their synthesis is often demanding. Computational tools suggesting macrocyclization based on a known binding mode and estimating their binding affinity could have a substantial impact on the medicinal chemistry design process. For both tasks, we established a workflow with high practical value. For five diverse pharmaceutical targets we show that the effect of macrocyclization on binding can be calculated robustly and accurately. Applying the method to macrocycles designed by LigMac, a search tool for de novo macrocyclization, our results suggest that we have a robust protocol in hand to design macrocycles and prioritize them prior to synthesis.