Identification of Potential Bioactive Phytochemicals for the Inhibition of Platelet-Derived Growth Factor Receptor β: An integrated docking and MD simulation approach

Abstract

Platelet-derived growth factor receptor beta (PDGFRβ) belongs to the receptor tyrosine kinase (RTK) protein family and is implicated in various diseases, including cancer. Its signaling pathway has been linked to various human meningioma and atherosclerosis. Due to its pivotal role in disease pathogenesis, PDGFRβ has emerged as a promising drug target in cancer therapy and the treatment of other disorders. This study aimed to identify potential PDGFRβ inhibitors through virtual screening of phytochemicals extracted from the IMPPAT database. The initial assessment involved applying the Lipinski rule-of-five to evaluate the physicochemical properties of the molecules. Subsequently, a comprehensive analysis encompassing binding affinity assessment, PAINS filter application, ADMET profiling, and PASS prediction was conducted. Among the screened compounds, Genostrychnine and Chelidonine exhibited remarkable affinity and specificity in their interactions with the PDGFRβ kinase domain. To gain insights into the temporal evolution and dynamics of these interactions, all-atom molecular dynamics (MD) simulations and essential dynamics analysis were employed. These computational techniques provided valuable insights into the behavior and stability of the PDGFRβ-ligand complexes over time. Based on our findings, we propose that Genostrychnine and Chelidonine merit further investigation through in vivo and in vitro studies to evaluate their potential for managing PDGFRβ-associated malignancies. In conclusion, this study underscores the potential of Genostrychnine and Chelidonine as promising PDGFRβ inhibitors. Further experimental investigations are required to validate their efficacy and assess their therapeutic potential for PDGFRβ-related diseases, with a particular focus on cancer management.