Lead phytochemicals and marine compounds against ceruloplasmin in cancer targeting

In silico docking studies serve as a swift and efficient means to sift through a vast array of natural and synthetic small molecules, aiding in the identification of potential inhibitors for cancer biomarkers. One such biomarker, ceruloplasmin (CP), has been implicated in various tumor types due to its overexpression, earning it recognition as a marker of aggressive tumors. This study focused on pinpointing inhibitors for the CP –Myeloperoxidase (MPO) interaction site, a complex formation known to impede HOCl production, a crucial process for inducing apoptotic cell death in tumor cells. The initial phase of our investigation involved in silico docking studies, which screened a diverse library of phytochemicals and marine compounds. Through this process, we identified several promising drug candidates based on their binding affinities. Subsequently, these candidates underwent rigorous filtration based on Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. Finally, we subjected the selected compounds to molecular dynamics (MDs) simulation to further assess their viability. Lycoperoside F, a steroidal alkaloid glycoside derived from tomatoes (Lycopersicon esculentum), stood out with notable interactions at the binding site. Another noteworthy compound was Xyloglucan (XG) oligosaccharides, predominantly found in the primary cell walls of higher plants. During the subsequent MDs simulations, these interactions were accompanied by highly stable root mean square deviation (RMSD) plots, signifying the consistency and robustness of the observed MDs behavior. XG oligosaccharides demonstrated the highest binding affinity with CP, reaffirming their potential as strong candidates. Additionally, Ardimerin digallate, known as a retroviral ribonuclease H inhibitor for HIV-1 and HIV-2, displayed favorable interactions at the MPO interaction site. Given that promising drug candidates must meet stringent criteria, including non-toxicity, effectiveness, specificity, stability and potency, these phytochemicals have the potential to progress to in vitro studies as CP inhibitors. Ultimately, this could contribute to the suppression of tumor growth, marking a significant step in cancer treatment research.
Communicated by Ramaswamy H. Sarma

计算机模拟分子对接研究（in silico docking studies）是快速高效筛选海量天然与合成小分子化合物的重要手段，可助力鉴定癌症生物标志物的潜在抑制剂。其中一种生物标志物为铜蓝蛋白（ceruloplasmin, CP），因其在多种肿瘤中高表达而与肿瘤发生密切相关，被视为侵袭性肿瘤的标志物。本研究聚焦于CP-髓过氧化物酶（Myeloperoxidase, MPO）相互作用位点的抑制剂筛选——该复合物的形成可抑制次氯酸（HOCl）的生成，而次氯酸是诱导肿瘤细胞凋亡的关键过程。
本研究的初始阶段为计算机模拟分子对接研究，对包含植物化学物与海洋来源化合物的多样化文库进行筛选，基于结合亲和力鉴定出数种颇具潜力的候选药物。随后，依据吸收、分布、代谢、排泄与毒性（ADMET）性质对这些候选药物进行严格筛选。最终，对筛选出的化合物开展分子动力学（MDs）模拟，以进一步评估其成药性。
其中，源自番茄（Lycopersicon esculentum）的甾体生物碱苷——番茄苷F（Lycoperoside F），在结合位点展现出显著的相互作用。另一值得关注的化合物为木葡聚糖（XG）寡糖，该物质主要存在于高等植物的初生细胞壁中。在后续的MDs模拟中，这些相互作用伴随高度稳定的均方根偏差（RMSD）曲线，表明模拟行为具有良好的一致性与稳健性。木葡聚糖寡糖与CP的结合亲和力最高，进一步证实了其作为强效候选药物的潜力。此外，作为HIV-1和HIV-2的逆转录病毒核糖核酸酶H抑制剂的Ardimerin二没食子酸酯（Ardimerin digallate），在MPO相互作用位点也展现出良好的相互作用。
鉴于极具潜力的药物候选物需满足严苛标准，包括无毒、高效、特异性强、稳定性佳与活性强劲，这些植物化学物具备作为CP抑制剂开展体外研究的潜力。最终，这或将助力肿瘤生长的抑制，为癌症治疗研究迈出重要一步。
由Ramaswamy H. Sarma转交