Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan.
Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia.
J Biomol Struct Dyn. 2024 Apr;42(7):3295-3306. doi: 10.1080/07391102.2023.2216758. Epub 2023 Jun 6.
MCM7 (Minichromosome Maintenance Complex Component 7) is a component of the DNA replication licensing factor, which controls DNA replication. The MCM7 protein is linked to tumor cell proliferation and has a function in the development of several human cancers. Several types of cancer may be treated by inhibiting the protein, as it is strongly produced throughout this process. Significantly, Traditional Chinese Medicine (TCM), which has a long history of clinical adjuvant use against cancer, is rapidly gaining traction as a valuable medical resource for the development of novel cancer therapies, including immunotherapy. Therefore, the goal of the research was to find small molecular therapeutic candidates against the MCM7 protein that may be used to treat human cancers. A computational-based virtual screening of 36,000 natural TCM libraries is carried out for this goal using a molecular docking and dynamic simulation technique. Thereby, ∼8 novel potent compounds i.e., ZINC85542762, ZINC95911541, ZINC85542617, ZINC85542646, ZINC85592446, ZINC85568676, ZINC85531303, and ZINC95914464 were successfully shortlisted, each having the capacity to penetrate the cell as potent inhibitors for MCM7 to curb this disorder. These selected compounds were found to have high binding affinities compared to the reference (AGS compound) i.e. < -11.0 kcal/mol. ADMET and pharmacological properties showed that none of these 8 compounds poses any toxic property (carcinogenicity) and have anti-metastatic, and anticancer activity. Additionally, MD simulations were run to assess the compounds' stability and dynamic behavior with the MCM7 complex for about 100 ns. Finally, ZINC95914464, ZINC95911541, ZINC85568676, ZINC85592446, ZINC85531303, and ZINC85542646 are identified as highly stable within the complex throughout the 100 ns simulations. Moreover, the results of binding free energy suggested that the selected virtual hits significantly bind to the MCM7 which implied these compounds may act as a potential MCM7 inhibitor. However, testing protocols are required to further support these results. Further, assessment through various lab-based trial methods can assist with deciding the action of the compound that will give options in contrast to human cancer immunotherapy.Communicated by Ramaswamy H. Sarma.
MCM7（微小染色体维持复合物成分 7）是 DNA 复制许可因子的一个组成部分，该因子控制着 DNA 的复制。MCM7 蛋白与肿瘤细胞增殖有关，在多种人类癌症的发生中具有一定功能。由于该蛋白在整个过程中大量产生，因此抑制该蛋白可能会治疗多种类型的癌症。值得注意的是，中药（TCM）作为一种具有抗癌临床辅助应用悠久历史的药物，正在迅速成为一种有价值的医学资源，可用于开发新的癌症治疗方法，包括免疫疗法。因此，本研究的目的是寻找针对 MCM7 蛋白的小分子治疗候选物，以用于治疗人类癌症。为了实现这一目标，采用分子对接和动态模拟技术，对 36000 种天然 TCM 文库进行了基于计算的虚拟筛选。由此，成功筛选出 8 种新型强效化合物，即 ZINC85542762、ZINC95911541、ZINC85542617、ZINC85542646、ZINC85592446、ZINC85568676、ZINC85531303 和 ZINC95914464，它们都具有穿透细胞的能力，作为 MCM7 的有效抑制剂，可抑制这种失调。与参比（AGS 化合物）相比，这些被选择的化合物具有更高的结合亲和力，即 <-11.0 kcal/mol。ADMET 和药理学特性表明，这 8 种化合物均无任何毒性（致癌性），且具有抗转移和抗癌活性。此外，还进行了 MD 模拟，以评估化合物在大约 100 ns 内与 MCM7 复合物的稳定性和动态行为。最后，确定 ZINC95914464、ZINC95911541、ZINC85568676、ZINC85592446、ZINC85531303 和 ZINC85542646 在整个 100 ns 模拟过程中在复合物内高度稳定。此外，结合自由能的结果表明，所选虚拟命中物与 MCM7 显著结合，这意味着这些化合物可能作为潜在的 MCM7 抑制剂发挥作用。然而，需要进一步的测试方案来支持这些结果。此外，通过各种基于实验室的试验方法进行评估，可以帮助确定化合物的作用，从而为人类癌症免疫疗法提供选择。
由 Ramaswamy H. Sarma 传达。
Comput Biol Chem. 2018-12-7
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