Almansour Nahlah Makki, Abdelrahman Alaa H M, Ismail Fagiree Ekram, Ibrahim Mahmoud A A
Department of Biology, College of Science, University of Hafr Al Batin, Hafr Al Batin, Saudi Arabia.
Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia, Egypt.
J Biomol Struct Dyn. 2023 Sep-Oct;41(16):7651-7664. doi: 10.1080/07391102.2022.2123397. Epub 2022 Sep 19.
Multidrug resistance (MDR) is a fundamental reason for the fiasco of carcinoma chemotherapy. A wide variety of anticarcinoma drugs are expelled from neoplasm cells through the ATP-binding cassette (ABC) transporter superfamily, rendering the neoplasm cells resistant to treatment. The ATP-binding cassette transporter G2 (ABCG2, gene symbol BCRP) is an ABC efflux transporter that plays a key function in MDR to antineoplastic therapies. For these reasons, the identification of medicaments as BCRP inhibitors could assist in discovering better curative approaches for breast cancer therapy. Because of the deficiency of prospective BCRP inhibitors, the SuperDRUG2 database was virtually screened for inhibitor activity towards the BCRP transporter using molecular docking computations. The most potent drug candidates were then characterized utilizing molecular dynamics (MD) simulations. Furthermore, molecular mechanics-generalized Born surface area (MM-GBSA) binding affinities of the most potent drug candidates were estimated. Based on the MM-GBSA binding affinities throughout 150 ns MD simulations, three drugs-namely zotarolimus (SD002595 temsirolimus (SD003393), and glecaprevir (SD006009)-revealed greater binding affinities towards BCRP transporter compared to the co-crystallized BWQ ligand with Δ values of -86.6 ± 5.6, -79.5 ± 8.0, -75.8 ± 4.6 and -59.5 ± 4.1 kcal/mol, respectively. The steadiness of these promising drugs bound with BCRP transporter was examined utilizing their structural and energetical analyses throughout a 150 ns MD simulation. To imitate the physiological environment, 150 ns MD simulations for the identified drugs bound with BCRP transporter were conducted in the 1-palmitoyl-2-oleoyl-phosphatidylcholine lipid bilayer. These findings identify zotarolimus, temsirolimus and glecaprevir as auspicious anti-MDR drug leads that warrant further experimental assays.Communicated by Ramaswamy H. Sarma.
多药耐药（MDR）是癌症化疗失败的一个根本原因。多种抗癌药物通过ATP结合盒（ABC）转运蛋白超家族从肿瘤细胞中排出，使肿瘤细胞产生耐药性。ATP结合盒转运蛋白G2（ABCG2，基因符号BCRP）是一种ABC外排转运蛋白，在对抗肿瘤治疗的多药耐药中起关键作用。基于这些原因，鉴定出作为BCRP抑制剂的药物有助于发现更好的乳腺癌治疗方法。由于缺乏前瞻性的BCRP抑制剂，利用分子对接计算在SuperDRUG2数据库中虚拟筛选针对BCRP转运蛋白的抑制剂活性。然后利用分子动力学（MD）模拟对最有潜力的候选药物进行表征。此外，还估计了最有潜力的候选药物的分子力学-广义玻恩表面积（MM-GBSA）结合亲和力。基于150 ns MD模拟中的MM-GBSA结合亲和力，与共结晶的BWQ配体相比，三种药物——即佐他莫司（SD002595）、替西罗莫司（SD003393）和格卡瑞韦（SD006009）——对BCRP转运蛋白显示出更高的结合亲和力，其Δ值分别为-86.6±5.6、-79.5±8.0、-75.8±4.6和-59.5±4.1 kcal/mol。在150 ns MD模拟中，通过对这些有前景的药物与BCRP转运蛋白结合的结构和能量分析，研究了它们结合的稳定性。为了模拟生理环境，在1-棕榈酰-2-油酰-磷脂酰胆碱脂质双层中对鉴定出的与BCRP转运蛋白结合的药物进行了150 ns MD模拟。这些发现确定佐他莫司、替西罗莫司和格卡瑞韦是有前景的抗多药耐药药物先导物，值得进一步的实验研究。由拉马斯瓦米·H·萨尔马传达。
