School of Basic Sciences and BioX Center, Indian Institute of Technology Mandi, VPO Kamand, Mandi, Himachal Pradesh, India.
Department of Biochemistry, North-Eastern Hill University, Umshing, Shillong, Meghalaya, India.
J Biomol Struct Dyn. 2022 Jul;40(10):4507-4515. doi: 10.1080/07391102.2020.1858966. Epub 2020 Dec 11.
The inherent ability of the cancer cells to resist chemotherapeutic agents is a major challenge in drug discovery. Chemotherapy is one of the most widely used treatment methods for cancer, but due to multidrug resistance (MDR) development in cancer cells, the healing procedure often fails. Various factors impart cancer resistance to cells; among them, P-glycoprotein (P-gp) overexpression is directly linked to MDR in cancer cells. P-gp leads to the efflux of drug molecules to the extracellular space. Several molecules have been reported to inhibit the P-gp activity. Among them, quercetin has revealed a great potential to modulate P-gp activity. However, the mechanistic understanding of quercetin induced modulation is not entirely elucidated. In the present work, we showed that quercetin binds in the interacting region between the transmembrane domain and nucleotide-binding domain out of the three plausible binding sites of P-gp and restrict the conformational change from inward- to outward-facing conformation of P-gp. Due to the absence of the inward-facing structure of human P-gp, we first modeled an inward-facing P-gp structure. Using molecular docking, the interacting residues of P-gp were identified, and the stability and interaction dynamics of the complex were studied using molecular dynamics simulation. Our work reveals the mechanistic understanding of quercetin induced modulation of P-gp and indicates its importance in cancer treatment.Communicated by Ramaswamy H. Sarma.
癌细胞对化疗药物的固有耐药性是药物发现的主要挑战。化疗是癌症最广泛使用的治疗方法之一，但由于癌细胞中多药耐药（MDR）的发展，治疗过程常常失败。多种因素赋予细胞抗癌能力；其中，P-糖蛋白（P-gp）过表达与癌细胞中的 MDR 直接相关。P-gp 导致药物分子外排到细胞外空间。已经报道了几种分子可以抑制 P-gp 活性。其中，槲皮素已显示出调节 P-gp 活性的巨大潜力。然而，槲皮素诱导调节的机制理解并不完全清楚。在本工作中，我们表明，槲皮素结合在 P-gp 的三个可能结合位点之外的跨膜域和核苷酸结合域之间的相互作用区域，并限制 P-gp 从内向到外向构象的构象变化。由于缺乏人 P-gp 的内向结构，我们首先构建了一个内向 P-gp 结构。使用分子对接，确定了 P-gp 的相互作用残基，并通过分子动力学模拟研究了复合物的稳定性和相互作用动力学。我们的工作揭示了槲皮素诱导的 P-gp 调节的机制理解，并表明其在癌症治疗中的重要性。由 Ramaswamy H. Sarma 交流。
