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KMID : 0614020030180010012
Journal of Pharmaceutical Sciences (C.N.U.)
2003 Volume.18 No. 1 p.12 ~ p.20
Molecular Dynamics Simulations for Enantioselectivity in β-blocker and β-cyclodextrin complex
Jang Suk-Young

Park Kyung-Lae
Abstract
Beta-blockers have been used in the treatment of hypertension, angina and cardiovascular disorder Their pharmacodynamic and pharmacokinetic characteristics between (R) and (S) enantiomers are different. We selected β-cyclodextrin (BCD) as a chiral selector and metoprolol (MT) and propranolol (PNP) as quest molecules to investigate mechanism for separation. The binding interactions and energetics in inclusion complex of (S)- and (R)-enatniomer in BCD were investigated by molecular dynamics (MD) simulation method. In the inclusion complex the guest molecules restrains the host molecule to a smaller range of atomic fluctuation due to the electrostatic interactions between polar groups of guest and BCD Free energy calculation for the transition of (S)- to (R)-form was performed using slow-growth method. The improper dihedral angle around the chiral center of (S)-form was perturbed to (R) form The thermodynamic integration gave a free energy change from (S)-MT-BCD to (R)-MT-BCD of 0.98 kJ/mol, which predicts the bigger stability of (R)-MT-BCD complex than that of (S)-isomer. In the case of PNP-BCD complex, a free energy change of 0.95 kJ/mol indicates that (S)-form complex was more stable than (R)-form complex.
KEYWORD
Beta-cyclodextrin, beta -blocker, enantioselectivity, free energy, molecular dynamics
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