Inhibition of P-Glycoprotein Mediated Efflux of Paclitaxel by Coumarin Derivatives in Cancer Stem Cells: An In Silico Approach
Inhibition of P-Glycoprotein Mediated Efflux of Paclitaxel by Coumarin Derivatives in Cancer Stem Cells: An In Silico Approach
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DOI：
10.2174/1386207319666160517115158
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发表时间：
2016-01-01
影响因子：
1.8
通讯作者：
Misra, Krishna
中科院分区：
文献类型：
--
作者：
Tripathi, Anushree;Misra, Krishna
众所周知，P-糖蛋白（P-gp）会导致癌细胞产生多药耐药性（MDR）。这种多重耐药性会导致癌症复发，这是癌症治疗的主要障碍。在具有自我更新潜力的癌症干细胞 (CSC) 群体中观察到高 P-gp 表达。早期发现并抑制这些CSC直接有利于癌症治疗。在这项研究中，香豆素衍生物用于抑制外排过程，从而提高紫杉醇 (PTX) 等各种药物的生物利用度。该药物最常用于治疗乳腺癌、卵巢癌、头颈癌。香豆素衍生物可通过 P-gp 介导的外排抑制和紫杉醇生物利用度增强来减少乳腺癌干细胞的生长。通过使用包括分子对接模拟和药效团研究在内的计算方法，很少有香豆素衍生物被发现是 P-gp 介导的外排的更潜在的抑制剂。基于高亲和力抑制剂，设计了新的香豆素衍生物并对接在P-gps活性位点空腔中。一些新设计的香豆素衍生物被发现更有效，因为它们对靶蛋白具有更高的结合亲和力。新设计的香豆素可用于抑制 P-gp 介导的外流，以提高紫杉醇的生物利用度，并可抑制乳腺癌干细胞的生长，这一发现对于设计有效的抗癌药物具有重要意义。
P-glycoprotein (P-gp) is well known to cause multidrug resistance (MDR) in cancer cells. This MDR leads to cancer recurrence which is a major obstacle in cancer treatment. High P-gp expression has been observed in the population of cancer stem cells (CSCs) having self-renewal potential. Early detection and inhibition of these CSCs is directly beneficial to cancer treatment. In this study coumarin derivatives are used to inhibit efflux process and thereby enhance bioavailability of various drugs like paclitaxel (PTX). This drug is most commonly used for the treatment of cancers of breast, ovary, head and neck. Coumarin derivatives can be used to reduce the growth of breast cancer stem cells through P-gp mediated efflux inhibition and paclitaxel bioavailability enhancement. With the use of computational approaches including molecular docking simulation and pharmacophore study, few coumarin derivatives have been found to be more potential inhibitors of P-gp mediated efflux. Based on high affinity inhibitors, new coumarin derivatives have been designed and docked at active site cavity of P-gps. Some newly designed coumarin derivatives were found to be more potent due to their higher binding affinity towards target protein. The finding that newly designed coumarins can be exploited for inhibition of P-gp mediated efflux in order to enhance paclitaxel bioavailability and can inhibit breast cancer stem cell growth is significant for designing potent anticancer drugs.