Drugs having a molecular weight >600-700 Da adopt a limited number of conformations in different environments. This allows them to behave as molecular chameleons that adapt to the environment, thereby combining high solubility with permeability across cell membranes and potent target binding. However, the understanding of the relationships between chemical structure, populated conformations, and different environments is lacking for this class of larger drugs. In addition, the complex and coupled interactions that govern macrocycle conformations usually result in minimum energy conformations (MECs) identified by molecular mechanics force fields from sampled ensembles showing large differences from the biologically relevant conformations. Instead, conformations resembling the biologically relevant ones have frequently been found at >10-15 kcal/mol above the MECs. However, in our recent case study with quantum mechanics for macrocyclic compounds, we were able to find relevant conformations within the RMSE <1 kcal/mol for macrocyclic compounds (Publication, also see Activity_Report_to_SNIC_202122-244.pdf). These results are encouraging and should be applied to a wider set of macrocyclic compounds. Using MD simulations and DFT calculations, we will investigate how similar molecules (only differences in stereo- and regio-chemistry) exhibit significant differences in cellular permeability. Finding the relevant conformations may help us to understand the permeability cliffs of macrocyclic compounds.
Sethio D#, Poongavanam V#, Tyagi M, Lindh R, Kihlberg J, Understanding and predicting macrocycle structure and flexibility in polar and apolar environments, Angewandte Chemie, 2022 (to be submitted). The SNIC allocation time has been acknowledged in the aforementioned article.