Enantioselective drug-protein interaction between mexiletine and plasma protein

The Journal of Pharmacy and Pharmacology
Lushan YuSu Zeng

Abstract

This study examined the interaction of mexiletine enantiomers with human plasma, human serum albumin (HSA), and human α1-acid glycoprotein (hAGP), and characterized the binding modes of mexiletine enantiomers with hAGP in the molecular level. Enantiomer separation of mexiletine was performed using precolumn derivatization chiral HPLC. The ultrafiltration technique was used to separate the free mexiletine in plasma matrix. Molecular dynamics simulations and free energy calculations were assessed using molecular mechanics and the generalized Born surface area method. Significant differences in enantioselective binding to human plasma were observed (R>S). The hAGP-mexiletine binding profile exhibited similar enantioselectivity (R>S) to that in human plasma, whereas HSA-mexiletine interaction was S>R at pH 7.4. Moreover, the results of comparative studies indicated that mexiletine had the highest binding affinity for F1-S, a variant of hAGP. Based on the computational studies, residues such as Arg90, Leu79, Ser89 and Phe89 showed an energy difference of more than -0.35 kcal/mol between the enantiomers. hAGP may be one of the key proteins leading to the enantioselective protein bindings of mexiletine in human plasma (R>S). The resid...Continue Reading

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Citations

Jul 16, 2013·Acta Pharmacologica Sinica·Qi ShenSu Zeng
Mar 7, 2014·Canadian Journal of Physiology and Pharmacology·Ana Leonor Pardo Campos GodoyVera Lucia Lanchote
Dec 12, 2012·British Journal of Pharmacology·J JohnD Liang
Apr 10, 2013·Biochimica Et Biophysica Acta·Shin-ichi Fujiwara, Takashi Amisaki

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