Gaussian accelerated molecular dynamics simulations facilitate prediction of the permeability of cyclic peptides

Despite their widespread use as therapeutics, clinical development of small molecule drugs remains challenging. Among the many parameters that undergo optimization during the drug development process, increasing passive cell permeability (i.e., log(P)) can have some of the largest impact on potency. Cyclic peptides (CPs) have emerged as a viable alternative to small molecules, as they retain many of the advantages of small molecules (oral availability, target specificity) while being highly effective at traversing the plasma membrane. However, the relationship between the dominant conformations that typify CPs in an aqueous versus a membrane environment and cell permeability remain poorly characterized. In this study, we have used Gaussian accelerated molecular dynamics (GaMD) simulations to characterize the effect of solvent on the free energy landscape of lariat peptides, a subset of CPs that have recently shown potential for drug development (Kelly et al., JACS 2021). Differences in the free energy of lariat peptides as a function of solvent can be used to predict permeability of these molecules, and our results show that permeability is most greatly influenced by N-methylation and exposure to solvent. Our approach lays the groundwork for using GaMD as a way to virtually screen large libraries of CPs and drive forward development of CP-based therapeutics.