多重耐药性（MDR）的特点是癌细胞对多种抗癌药物产生耐药性。 MDR 表型的主要机制是通过促进癌细胞的活性药物流出来过度表达 ATP 结合盒 (ABC) 转运蛋白。一些小分子蛋白激酶抑制剂已被发现通过抑制 ABC 转运蛋白作为底物或调节剂来克服 MDR。本研究调查了 58 种 FDA 批准的抗癌激酶抑制剂针对三种多药耐药性相关蛋白的化学活性。研究的蛋白质是 ATP 结合盒亚家族 B 成员 1 (ABCB1)、ATP 结合盒亚家族 C 成员 1 (ABCC1) 和 ATP 结合盒超家族 G 成员 2 (ABCG2)。蛋白质的药物结合域和 ATP 结合位点被认为是激酶抑制剂的可能靶点。采用高通量虚拟筛选和分子对接来寻找命中药物，并利用分子动力学（MD）模拟进一步评估具有最高结合亲和力的药物。虚拟筛选显示，几种激酶抑制剂可以被认为是ABCB1、ABCC1和ABCG2的潜在抑制剂，其中larotrectinib、entrectinib和infigratinib分别表现出最高的结合亲和力。根据MD模拟获得的结果，这些药物可以与靶蛋白的必需残基形成强烈的相互作用。计算机研究表明，larotrectinib、entrectinib 和 infigratinib 可以靶向所研究蛋白质的关键残基。因此，这些批准的激酶抑制剂可以被认为是通过靶向这些转运蛋白来治疗 MDR 癌症的潜在疗法。Ramaswamy H. Sarma 通讯。

Multiple drug resistance (MDR) is characterized by the resistance of cancer cells to a broad spectrum of anticancer drugs. The main mechanism underlying the MDR phenotype is the overexpression of ATP-binding cassette (ABC) transporters by promoting active drug efflux from cancer cells. Some small-molecule protein kinase inhibitors have been found to overcome MDR by inhibiting ABC transporters as substrates or modulators. This study investigated the chemical activity of 58 FDA-approved anticancer kinase inhibitors against three multidrug resistance-related proteins. The studied proteins are ATP-Binding Cassette Sub-Family B Member 1 (ABCB1), ATP-Binding Cassette Subfamily C Member 1 (ABCC1), and ATP-binding cassette superfamily G member 2 (ABCG2). The drug-binding domain and ATP binding sites of the proteins were considered the kinase inhibitors' probable target. High-throughput virtual screening and molecular docking were employed to find the hit drugs, and the drugs with the highest binding affinity were further evaluated using the molecular dynamics (MD) simulation. The virtual screening revealed that several kinase inhibitors could be considered potential inhibitors of ABCB1, ABCC1, and ABCG2, among which larotrectinib, entrectinib, and infigratinib showed the highest binding affinity, respectively. Based on the obtained results from MD simulation, these drugs can form strong interactions with the essential residues of the target proteins. In silico investigation revealed that larotrectinib, entrectinib, and infigratinib can target the key residues of the studied proteins. Therefore, these approved kinase inhibitors could be considered potential therapies for MDR cancers by targeting these transporters.Communicated by Ramaswamy H. Sarma.