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首页> 外文期刊>Bioorganic and medicinal chemistry >Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors.
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Molecular docking studies and in vitro screening of new dihydropyridine derivatives as human MRP1 inhibitors.

机译：作为人MRP1抑制剂的新型二氢吡啶衍生物的分子对接研究和体外筛选。

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The overexpression of multidrug resistance protein 1 (MRP1) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Circumvention of MDR by combination of chemosensitizers with antitumor compounds is a new field of investigation in cancer chemotherapy. Much effort has been put-in recently to identify the modulators/inhibitors of MRP1 to overcome the MDR. 1,4-Dihydropyridine (DHP) derivatives are indicated to be a new class of MRP1 inhibitors in cancer treatment. Molecular docking studies were carried out on 48 newly synthesized DHP derivatives with the crystal structure of MRP1 to gain some structural insights on the binding mode and possible interactions with the active site of MRP1 (NBD1). The 10 top-ranked molecules were selectively evaluated, experimentally for their MRP1 inhibitory effect using the insect cell membrane MRP1 ATPase assay. The inhibitory capacity (IC(50) concentrations) of the test compounds was compared with the reported IC(50)- or the K(i)-concentrations for benzbromarone, a standard MRP1 inhibitor. Amongst the compounds tested, compounds IA(1) and IIA(5) were found to exhibit a potent MRP1 inhibitory action with IC(50) values of 20+/-4 and 14+/-2 muM (mean+/-SD), respectively as compared to benzbromarone (IC(50)=4 muM). The compound IIA(5), in particular was found to be more potent than IA(1) in accordance with the docking results. These new DHP derivatives possess promising characteristics for their development as MDR reversal agents.
机译：肿瘤细胞过表达多药耐药蛋白 1 （MRP1） 导致对结构无关的抗癌药物产生多药耐药 （MDR）。通过将化学增敏剂与抗肿瘤化合物联合使用来规避MDR是癌症化疗的一个新研究领域。最近，人们付出了很多努力来确定MRP1的调节剂/抑制剂，以克服MDR。1,4-二氢吡啶 （DHP） 衍生物被证明是癌症治疗中的一类新型 MRP1 抑制剂。对48个新合成的具有MRP1晶体结构的DHP衍生物进行了分子对接研究，以获得一些关于MRP1（NBD1）结合模式和可能与活性位点相互作用的结构见解。选择性地评估排名靠前的 10 个分子，使用昆虫细胞膜 MRP1 ATP 酶测定法对它们的 MRP1 抑制作用进行实验。将测试化合物的抑制能力（IC（50）浓度）与报告的IC（50）-或苯溴马隆（一种标准MRP1抑制剂）的K（i）浓度进行比较。在测试的化合物中，化合物IA（1）和IIA（5）表现出有效的MRP1抑制作用，IC（50）值分别为20+/-4和14+/-2 μM（平均值+/-SD），而苯溴马隆（IC（50）=4 μM）。根据对接结果，特别是化合物IIA（5）比IA（1）更有效。这些新的DHP衍生物具有作为MDR逆转剂开发的前景。

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