Structure-Based Molecular Docking and ADME Profiling of Novel Thienopyrimidines as Dual VEGFR/EGFR Inhibitors in Colorectal Cancer

Priya, A and Nargund, Shachindra L. and Kumar N, Mahesh and Gote, Sharmila A. (2025) Structure-Based Molecular Docking and ADME Profiling of Novel Thienopyrimidines as Dual VEGFR/EGFR Inhibitors in Colorectal Cancer. World Journal of Biology Pharmacy and Health Sciences, 23 (1). pp. 528-536. ISSN 2582-5542

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally, contributing to nearly 10% of all cancer cases and 9.4% of cancer mortalities, as reported by recent GLOBOCAN data. Targeting receptor tyrosine kinases such as vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) has become a vital strategy in cancer therapeutics due to their key roles in tumor angiogenesis and cell proliferation. In this study, a series of novel thienopyrimidine derivatives were computationally evaluated for their potential as dual inhibitors of VEGFR and EGFR using a structure-based drug design approach. The crystal structures of VEGFR2 (PDB ID: 6GQP) and EGFR (PDB ID: 5D41) were retrieved from the Protein Data Bank and prepared using AutoDock Tools. Thienopyrimidine derivatives were designed using ChemDraw, energy-minimized, and converted into 3D structures. Molecular docking simulations were conducted using AutoDock Vina within PyRx, and protein-ligand interactions were analyzed using PyMOL and Discovery Studio. Docking results revealed that compounds PAS1 and PAS9 exhibited the highest binding affinities toward both EGFR (–8.7 kcal/mol) and VEGFR (–8.6 and –8.0 kcal/mol, respectively), outperforming the reference drug Lenvatinib (–8.3 and –7.9 kcal/mol). Pharmacokinetic properties assessed using SwissADME indicated that most compounds complied with Lipinski’s rule of five, and demonstrated favorable absorption, bioavailability, and blood-brain barrier permeability. Overall, this study suggests that thienopyrimidine scaffolds possess promising dual-inhibitory potential and favorable drug-like properties, supporting their development as targeted therapies for colorectal cancer.