Pharmacokinetics and drug-likeness of anti-cancer traditional Chinese medicine: molecular docking and molecular dynamics simulation study

Abstract

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, in vitro 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