Abstract

P-glycoprotein (ABCB1) and cytochrome P450 3A4 (CYP3A4) metabolize almost all known human immunodeficiency virus' protease inhibitor drugs (PIs). Over induction of these proteins’ activities has been linked to rapid metabolism of PIs which are then pumped out of the circulatory system, eventually leading to drug-resistance in HIV-positive patients. This study aims to determine, with the use of computational tools, the inhibitory potential of four phytochemical compounds (PCs) (epigallocatechin gallate (EGCG), kaempferol-7-glucoside (K7G), luteolin (LUT) and ellagic acid (EGA)) in inhibiting the activities of these drug-metabolizing proteins. The comparative analysis of the MM/GBSA results revealed that the binding affinity (ΔG_bind) of EGCG and K7G for CYP3A4 and ABCB1 are higher than LUT and EGA and fall between the ΔG_bind of the inhibitors of CYP3A4 and ABCB1 (Ritonavir (strong inhibitor) and Lopinavir (moderate inhibitor)). The structural analysis (RMSD, RMSF, RoG and protein-ligand interaction plots) also confirmed that EGCG and K7G showed similar inhibitory activities with the inhibitors. The study has shown that EGCG and K7G have inhibitory activities against the two proteins and assumes they could decrease intracellular efflux of PIs, consequently increasing the optimal concentration of PIs in the systemic circulation.

Communicated by Ramaswamy H. Sarma

摘要

P-糖蛋白 (ABCB1) 和细胞色素 P450 3A4 (CYP3A4) 代谢几乎所有已知的人类免疫缺陷病毒的蛋白酶抑制剂药物 (PI)。过度诱导这些蛋白质的活性与 PIs 的快速代谢有关，然后 PIs 被泵出循环系统，最终导致 HIV 阳性患者产生耐药性。本研究旨在使用计算工具确定四种植物化学化合物 (PC)（表没食子儿茶素没食子酸酯 (EGCG)、山奈酚-7-葡萄糖苷 (K7G)、木犀草素 (LUT) 和鞣花酸 (EGA)）的抑制潜力抑制这些药物代谢蛋白的活性。MM / GBSA结果的比较分析表明结合亲和力（ΔG_结合) EGCG 和 K7G 对 CYP3A4 和 ABCB1 的影响高于 LUT 和 EGA，并且介于CYP3A4 和 ABCB1 抑制剂（利托那韦（强抑制剂）和洛匹那韦（中度抑制剂））的 ΔG_{结合之间。}结构分析（RMSD、RMSF、RoG 和蛋白质-配体相互作用图）也证实 EGCG 和 K7G 显示出与抑制剂相似的抑制活性。该研究表明，EGCG 和 K7G 对这两种蛋白质具有抑制活性，并假设它们可以减少 PIs 的细胞内流出，从而增加 PIs 在体循环中的最佳浓度。

由 Ramaswamy H. Sarma 传达