In silico study to identify novel NEK7 inhibitors from natural source by a combination strategy

Abstract Cancer remains a significant health problem and stands as one of the primary causes of death worldwide. NEK7, a NIMA-related protein kinase, plays a crucial role in spindle assembly and cell division. Dysregulation of the NEK7 protein contributes to the development and progression of various malignancies, such as colon cancer and breast cancer. Therefore, the inhibition of NEK7 shows promise as a potential clinical target for anticancer therapy. Nevertheless, there is a dearth of high-quality NEK7 inhibitors. In this study, we utilized virtual screening, molecular docking, silicon-based pharmacokinetics, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA)-based binding free energy calculations to comprehensively analyze effective natural inhibitors that target NEK7 within the current framework. By employing molecular docking, including semi-flexible and flexible docking methods, we identified three natural products as hit compounds with binding modes similar to the active control dabrafenib. ADME/T predictions indicated that these hit molecules exhibited lower toxicity when administered orally. Additionally, through DFT calculations, we determined that the popular compound (-)-balanol possessed high chemical activity. Finally, 100 ns molecular dynamics simulations and energy decomposition revealed that the hit compounds displayed superior binding energy compared to the active control and demonstrated higher affinity. Based on the findings of our current research, we conclude that these newly discovered natural inhibitors may serve as parent structures for the development of more potent derivatives with promising biological activities. However, further experimental validation is necessary as part of subsequent investigations.