While macrocycles can display improvements compared to their equivalent ring opened analogue, the synthetic challenges associated with their design and synthesis make them higher risk strategies. To mitigate the risk associated with higher investment in synthetic resources, higher scrutiny at the planning phase of the process is recommended, so that efforts can be focused on prioritizing ligand designs with higher chance of succeeding.

In this study we applied Electrostatic Complementarity™ (EC), 3D-Field Quantitative Structure-Activity Relationship (3D-QSAR), and Free Energy Perturbation (FEP) methods, all available in Flare™, for the profiling of a dataset of known macrocycle JAK2 ligands. Our intent was to develop a prioritization workflow for the selection of macrocyclic designs for synthesis. The importance of understanding the 3D conformation and flexibility of a ligand is demonstrated, with these effects having a significant implication on the accuracy of predictions.

By presenting this study, we will show you that computer-aided drug design (CADD) can be used to prioritize challenging ligands for synthesis, with EC, 3D Field QSAR, and FEP all providing valuable insights. This approach facilitates flexible evaluation of chemically diverse molecules, providing a streamlined workflow to guide and prioritize the design of novel therapeutic molecules as well as to help organizations de-risk projects, shorten development timelines, and increase the probability of success.