Structure-based in-silico identification of natural compounds as potential inhibitors of ran GTPase for breast cancer treatment

Abstract

Genomic instability segregation significantly contributes to the cellular mechanisms that affect the transition from normal to neoplastic cell proliferation, which enhances the ability of cancer cells to spread to distant sites and cause secondary growth, leading to cancer development. Mutated chromosome segregation can result from various factors, such as compromised centromere duplication, and disrupted assembly of the mitotic spindle. Due to metastasis, cancer is known to be associated with an increased mortality rate among patients. Hence, to suggest the development of more effective treatment strategies, it is essential to identify biomolecular and genetic markers that can serve as prognostic and predictive indicators in the progression of breast cancer. For instance, Ran GTPase (1K5G) has been recognised as a potential contributor to breast cancer. Ran, a small GTPase, plays a role in various cellular processes. The primary objective of the study was to assess the potential therapeutic advantages of natural compounds against breast cancer, with a specific focus on the Ran GTPase protein. The approach involved a virtual screening method to identify the most efficient compounds from the NP-lib database at the MTiOpenScreen website against 1K5G. Following the screening process, the top three compounds were selected for molecular docking along with a co-crystallized GUANOSINE-5′-DIPHOSPHATE (GDP) inhibitor serving as a reference compound. In the active site of 1K5G against the reference inhibitor GDP, each compound showed significant docking energy between −9.1 and −8.9 kcal/mol. Further, the study also used molecular dynamic simulation (100 ns) to analyze the stability and physical movements of atoms and molecules. The compounds within this group can disrupt interactions involving the Ran GTPase protein within cells.