ORG-317 Repurposing as a Potential Agonist Targeting TMEM236 in Colorectal Cancer Treatment: Insights from Molecular Dynamics Simulation, Principal Component Analysis, and Free Energy Landscape Study

Background and objective: Colorectal Cancer (CRC) affects the colon and rectum part of the digestive system and is a significant global health concern, with approximately 1.1 million new cases annually. It ranks second in cancer-related deaths. Studies have shown future projections of CRC cases to enhance at a worrisome rate, estimating 3.2 million new cases and 1.6 million deaths worldwide by 2040. Studies have shown the downregulation of TMEM236 in CRC, and this study aimed to find the agonist to restore the function of TMEM236 via the drug repurposing method. Methods: The different molecular and structural level analyses were performed to understand how the TMEM236 expression can be restored. To obtain the molecular level data, the following analyses were employed to understand the binding affinity and agonistic behaviour of the screened drugs: molecular docking, oral toxicity prediction, Molecular Dynamics (MD) simulation, Free Energy Landscape (FEL) analysis, and g_mmpbsa. Results: The molecular docking, oral toxicity, and molecular interaction analyses have identified db06435, db05423, and db15197 drugs from the DrugBank database to either belong to an approved or investigational class of drugs as a potential agonist for TMEM236. The MD simulation and PCA analysis had shown db05423 (ORG-317) to exhibit stable interaction with TMEM236 protein. Similar results were obtained through FEL analysis. Conclusion: The downregulation of TMEM236 expression and its constant binding affinity with db05423 during MD simulation suggest that this drug may restore the diminished function and expression of TMEM236. Additionally, it could function as an agonist and can be used for CRC treatment.