Identification of Potential Inhibitors of TGFβR1 for the Treatment of Cancer through Structure-Based Virtual Screening and Molecular Dynamics Simulations.

Globally, cancer is one of the leading causes of death. Resistance to conventional medications, such as chemotherapy and radiation, continues to be a significant challenge in the treatment of cancer despite the availability of numerous medicines. Therefore, the highest priority is to hunt for new therapeutic agents. Transforming growth factor-beta is a pivotal regulatory cytokine that exerts significant influence over cellular processes, particularly emphasizing its role in facilitating and modulating cell proliferation. TGF-β receptor 1, identified as the most promising active site of the TGF-β signaling, is a potent drug target site that has garnered wide attention for developing new anticancer agents. The present investigation investigates the potential natural products as TGFβR1 inhibitors. The SB431542 complexed TGFβR1 protein model was used to screen the natural product database to obtain a compound with high binding potential. NPC247629 has emerged as the best-scored compound among all the screened compounds, demonstrating the highest affinity towards the TGFβR1 regarding docking score -17.54 kcal/mol. The all-atoms MD simulation study indicated that all proposed hits are retained inside the receptor in dynamic states. Additionally, principal component and free energy landscape analysis were performed to explore the binding mechanism of top-hit natural products. The best-screened hits, NPC247629 and NPC60735, have excellent binding affinity and hold a massive potential for TGFβR1 inhibition, paving the way for promising future investigations in cancer treatment.