Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran.
Sci Rep. 2022 Aug 11;12(1):13674. doi: 10.1038/s41598-022-17994-3.
Understanding the precise mechanistic details of the possible binding and transport of antiseizure medications (ASMs) through the P-glycoprotein (P-gp) efflux pump is essential to find strategies for the treatment of patients with epilepsy resistant to ASMs. In the present work, conventional molecular dynamics, binding free energy calculations, steered molecular dynamics and umbrella sampling were applied to study the interactions of levetiracetam and brivaracetam with P-gp and their possible egress path from the binding site. Comparative results for the control drugs, zosuquidar and verapamil, confirmed their established P-gp inhibitory activity. Brivaracetam, a non-substrate of P-gp, demonstrated stronger static and dynamic interactions with the exporter protein, than levetiracetam. The potential of mean force calculations indicated that the energy barriers through the ligand export were the lowest for levetiracetam, suggesting the drug as a P-gp substrate with facile passage through the transporter channel. Our findings also stressed the contribution of nonpolar interactions with P-gp channel lining as well as with membrane lipid molecules to hamper the ASM efflux by the transmembrane exporter. Appropriate structural engineering of the ASMs is thus recommended to address drug-resistant epilepsy.
了解抗癫痫药物（ASMs）通过 P 糖蛋白（P-gp）外排泵的可能结合和转运的精确机制细节对于寻找治疗对 ASMs 耐药的癫痫患者的策略至关重要。在本工作中，应用传统分子动力学、结合自由能计算、导向分子动力学和伞状采样来研究左乙拉西坦和布瓦西坦与 P-gp 的相互作用及其从结合位点可能的外排途径。对照药物佐西曲坦和维拉帕米的比较结果证实了它们对 P-gp 的抑制活性。布瓦西坦是 P-gp 的非底物，与外排蛋白的静态和动态相互作用强于左乙拉西坦。平均力势计算表明，通过配体出口的能量屏障对于左乙拉西坦最低，表明该药物是一种易于通过转运体通道的 P-gp 底物。我们的研究结果还强调了与 P-gp 通道衬里以及与膜脂分子的非极性相互作用对阻碍跨膜外排泵的 ASM 外排的贡献。因此，建议对 ASMs 进行适当的结构工程，以解决耐药性癫痫。
