School of Chemistry and Molecular Biosciences (SCMB) , University of Queensland , Brisbane , QLD 4072 , Australia.
Research School of Chemistry (RSC) , Australian National University , Canberra , ACT 2601 , Australia.
J Chem Inf Model. 2019 May 28;59(5):2287-2298. doi: 10.1021/acs.jcim.8b00624. Epub 2019 Jan 2.
The human multidrug transporter P-glycoprotein (P-gp) transports over 200 chemically diverse substrates, influencing their bioavailability and tissue distribution. Pharmacological studies have identified both competitive and noncompetitive P-gp substrates, but neither the precise location of the substrate binding sites, nor the basis of competitive and noncompetitive interactions has been fully characterized. Here, potential of mean force (PMF) calculations are used to identify the transport-competent minimum free energy binding locations of five compounds, Hoechst 33342, Rhodamine 123, paclitaxel, tariquidar, and verapamil to P-gp. Unrestrained molecular dynamics simulations were also performed to confirm the substrates were stable in the energy wells determined using the PMF calculations. All compounds had energy minima within the P-gp transmembrane (TM) pore. For Hoechst 33342 and Rhodamine 123, a second minimum outside the TM pore was also identified. Based on this and previous studies of nicardipine and morphine [ Subramanian et al. J. Chem. Inf. Model. 2015 , 55 , 1202 ], a general scheme that accounts for the observed noncompetitive and competitive substrate interactions with P-gp is proposed.
人多药耐药蛋白（P-gp）转运超过 200 种化学结构各异的底物，影响其生物利用度和组织分布。药理学研究已经确定了竞争性和非竞争性的 P-gp 底物，但底物结合位点的确切位置以及竞争性和非竞争性相互作用的基础尚未完全阐明。在这里，平均力势（PMF）计算被用于鉴定五种化合物，即 Hoechst 33342、Rhodamine 123、紫杉醇、tariquidar 和 verapamil 与 P-gp 的转运能力最低自由能结合位置。还进行了无约束的分子动力学模拟，以确认使用 PMF 计算确定的能量阱中底物的稳定性。所有化合物在 P-gp 跨膜（TM）孔内都有能量最小值。对于 Hoechst 33342 和 Rhodamine 123，还在 TM 孔外确定了第二个最小值。基于这一点以及先前关于尼卡地平（nicardipine）和吗啡的研究[Subramanian 等人，J. Chem. Inf. Model. 2015, 55, 1202]，提出了一种可以解释观察到的与 P-gp 的非竞争性和竞争性底物相互作用的通用方案。
