Department of Biological Sciences, Western Illinois University, Macomb, IL, USA.
Department of Chemistry, Mississippi University for Women, Columbus, MS, USA.
J Biomol Struct Dyn. 2023;41(24):15610-15624. doi: 10.1080/07391102.2023.2191133. Epub 2023 Mar 19.
Pancreatic ductal adenocarcinoma is an aggressive malignancy usually detectable at the advanced stage, with a 5-year survival rate of less than 8%. It has been reported that a gene called tumor-protein 63 (TP63) is expressed in an aggressive form of pancreatic cancer with a squamous signature. Thus, inhibiting the activity of p63 can be a means of treating and managing PDA. Different studies have shown that plant constituents are rich and can be a promising source for discovering drug candidates. The extract from mistletoe () is known to contain anticancer compounds; however, the specific molecular mechanism of the bioactive compounds is unknown. This study examines the pancreatic cancer therapeutic potential of the bioactive compounds in the flavonoid and phenolic acid constituents of mistletoe by adopting structural bioinformatics and advanced theoretical chemistry techniques via molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, pharmacokinetic analysis, and density functional theory analysis. The six best compounds from the flavonoid constituent with the highest binding affinity ranging from -6.8 kcal/mol to -6.7 kcal/mol were selected with the control gemcitabine (-5.5 kcal/mol) for further computational analysis after molecular docking. Furthermore, MM/GBSA calculation showed the highest binding energy for the selected docked compounds, which validates their inhibitory potential. Hence, the molecular dynamics simulation, post-simulation analysis, pharmacokinetics model, and DFT results showed that mistletoe compounds are reliable due to their stable interaction with the target protein and drug-likeness properties.Communicated by Ramaswamy H. Sarma.
胰腺导管腺癌是一种侵袭性恶性肿瘤，通常在晚期才能被检测到，其 5 年生存率低于 8%。据报道，一种名为肿瘤蛋白 63（TP63）的基因在具有鳞状特征的侵袭性胰腺癌中表达。因此，抑制 p63 的活性可能是治疗和管理胰腺导管腺癌的一种手段。不同的研究表明，植物成分丰富，是发现药物候选物的有前途的来源。众所周知，槲寄生的提取物含有抗癌化合物；然而，生物活性化合物的具体分子机制尚不清楚。本研究通过采用结构生物信息学和先进的理论化学技术，包括分子对接、分子动力学模拟、分子力学/广义 Born 表面积（MM/GBSA）计算、药代动力学分析和密度泛函理论分析，研究了槲寄生中类黄酮和酚酸成分的生物活性化合物对胰腺癌细胞的治疗潜力。从类黄酮成分中选择了 6 种结合亲和力最高的化合物，其结合亲和力范围为-6.8 kcal/mol 至-6.7 kcal/mol，与对照吉西他滨（-5.5 kcal/mol）一起进行进一步的计算分析。此外，MM/GBSA 计算显示所选对接化合物的结合能最高，验证了它们的抑制潜力。因此，分子动力学模拟、模拟后分析、药代动力学模型和 DFT 结果表明，由于槲寄生化合物与靶蛋白的稳定相互作用和类药性，它们是可靠的。Ramaswamy H. Sarma 通讯。
