High throughput evaluation of macrocyclization strategies for conformer stabilization

While macrocyclization of a linear compound to stabilize a known bioactive conformation can be a useful strategy to increase binding potency, the difficulty of macrocycle synthesis can limit the throughput of such strategies. Thus computational techniques may offer the higher throughput required to screen large numbers of compounds. Here we introduce a method for evaluating the propensity of a macrocyclic compound to adopt a conformation similar that of a known active linear compound in the binding site. This method can be used as a fast screening tool for prioritizing macrocycles by leveraging the assumption that the propensity for the known bioactive substructural conformation relates to the affinity. While this method cannot to identify new interactions not present in the known linear compound, it could quickly differentiate compounds where the three dimensional geometries imposed by the macrocyclization prevent adoption of conformations with the same contacts as the linear compound in their conserved region. Here we report the implementation of this method using an RMSD-based structural descriptor and a Boltzmann-weighted propensity calculation and apply it retrospectively to three macrocycle linker optimization design projects. We found the method performs well in terms of prioritizing more potent compounds.