Modulation of the Stereoselective Transport of Brivaracetam Diastereomers in Cyclopeptide Nanotubes through Side-Chain Polarity

Stereoselective separation is of considerable importance in pharmaceutical science because the biological activity of many drugs depends on their stereochemical configuration. Cyclopeptide nanotubes (CPNs), with their tunable structures and chiral cavities, offer promising platforms for chiral recognition and stereoisomer separation. However, the influence of side-chain polarity on the molecular recognition and discriminatory behavior of CPNs remains largely unexplored. Herein, the effect of side-chain polarity in three different CPNs on the discrimination of Brivaracetam (BVT) and its diastereomer was investigated using steered molecular dynamics (SMD) simulations. Three CPNs with distinct polarities were considered: a reference CPN with a balanced distribution of polar and nonpolar side chains, together with two analogues of higher and lower polarity. The simulations were designed in three complementary phases to examine stereoisomer transport through different regions of the nanotube. Phases 1 and 3 investigated the passage of stereoisomers along the nanotube wall, whereas phase 2 focused on their translocation through the central cavity. Interestingly, polar side-chain groups generally enhanced diastereomeric discrimination, although the extent of this effect depended on the simulation conditions and transport pathway. Along the nanotube wall, polar CPNs showed enhanced discrimination, particularly under unconstrained simulation conditions. In contrast, the CPN with balanced side-chain polarity provided the greatest discrimination during translocation through the central cavity. Overall, these findings demonstrate that subtle modifications of external side-chain functionality can markedly alter diastereomeric discrimination during stereoisomer transport through CPNs, highlighting the important role of the nanotube exterior in modulating chiral recognition.