Molecular modeling study to unravel complexation of daclatasvir and its enantiomer by β-cyclodextrins. Computational analysis using quantum mechanics and molecular dynamics

A computational study was performed to unravel mechanisms underlying capillary electrophoresis enantioseparations of daclatasvir and its (R,R,R,R)-enantiomer with native and methylated β-cyclodextrins (β-CDs) as chiral selectors. Considering the enantioseparation results as benchmark, the structures of β-CD and seven methylated β-CDs were optimized by quantum mechanics, and their topography and computed molecular properties were compared. Furthermore, the electron charge density distribution of the macrocycles was also evaluated by calculating the molecular electrostatic potential of pivotal regions of native and methylated β-CDs. The function of hydrogen bonds in the complexation process of daclatasvir and the CDs was derived from quantum mechanics analysis and confirmed by molecular dynamics, as orthogonal computational techniques. The presence of a round-shaped cavity in the CDs used as chiral selector appeared as a necessary requirement for the enantioseparation of daclatasvir and its (R,R,R,R)-enantiomer. In this regard, it was confirmed that the round shape of the CDs is sustained by hydrogen bonds formed between adjacent glucopyranose units and blocking rotation of the linking glycosidic bonds. The presence of hydroxy groups at the 6-position of the glucopyranose units and the concurrent absence of hydroxy groups at the 2-position were evidenced as important factors for enantioseparation of daclatasvir and its enantiomer by methylated β-CDs.