Molecular Dynamics and Experimental Validation of Natural Products from Chuanxiong Rhizoma as VEGFR2 Inhibitors for nAMD Therapy.

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly worldwide. Neovascular AMD (nAMD) is a significant subtype of AMD, responsible for the blindness of over 90% of patients with AMD. The hallmark of nAMD is choroidal angiogenesis dysregulation, a condition that can result in severe inflammation, leakage, and bleeding, ultimately leading to a precipitous decline in visual acuity. Inhibition of the vascular endothelial growth factor (VEGF) pathway has been proven to be an effective therapeutic strategy for this disease. Intraocular injection of anti-VEGF macromolecule drugs is a clinical therapy for this disease, but it has shortcomings, such as severe side effects, high cost, long treatment cycle, and complex administration methods. Consequently, the identification of novel small-molecule drugs and the development of innovative delivery mechanisms are of paramount importance for the treatment of this condition. Chuanxiong Rhizoma (CX), a type of traditional Chinese medicine (TCM), has been employed in the treatment of vascular-related diseases. Contemporary pharmacological research has demonstrated that CX contains a substantial quantity of natural compounds that exhibit anti-VEGF activity. In this study, we employed molecular simulation docking and molecular dynamics (MD) to examine the anti-VEGFR2 effects of 10 natural compounds derived from CX. Sorafenib was selected as the reference ligand, which is a marketed VEGFR2 inhibitor for cancer treatment. As a DFG-out inhibitor, sorafenib stabilizes the inactive conformation of the kinase by binding to an allosteric site near the ATP-binding pocket. In our research, natural products exhibiting a strong binding affinity were identified using computer-simulated docking technology and detailed binding sites were predicted. The findings of the research indicate that apigenin exhibits the strongest affinity for the VEGFR2 receptor with the formation of three hydrogen bonds. The molecular docking results indicate that the CYS919 and ASP1046 amino acid residues of VEGFR2 are the primary groups that form hydrogen bonds with the ligands. Furthermore, the AutoQSAR module of Schrödinger Suite predicted apigenin to have the highest predicted pIC