Integrated Virtual Screening of NPACT-Derived Phytochemicals as Potential FGFR1 Inhibitors for Cholangiocarcinoma Therapy: Molecular Docking, ADMET, MM-GBSA, and Molecular Dynamics

Abstract

Bile duct cancer (cholangiocarcinoma) is a rare but aggressive malignancy with a poor prognosis and limited treatment options. Fibroblast growth factor receptor 1 (FGFR1), a key regulator of tumour growth and angiogenesis, has been identified as a plausible therapeutic target. Due to the limitations in the safety and selectivity of existing inhibitors, there is a growing interest in exploring natural compounds as alternative drug lead candidates. This study aimed to identify and evaluate plant-derived phytochemicals as potential FGFR1 inhibitors for the treatment of cholangiocarcinoma using an integrated computer-aided drug design approach. A structure-based virtual screening of 67 phytochemicals from the NPACT database was conducted. Molecular docking against FGFR1 (PDB ID: 7WCL) using iGEMDock and Molecular Operating Environment (MOE) identified 17 hit compounds with binding energies ranging from −12.3 to −9.8 kcal/mol (iGEMDock) and −9.7 to −8.0 kcal/mol (MOE), outperforming Pemigatinib (−9.7 and −7.5 kcal/mol). Lipinski’s Rule of Five narrowed them down to seven drug-like candidates. ADMET screening further identified four compounds as pharmacokinetically acceptable. MM-GBSA analysis revealed that 10-Hydroxytrilobacin (-47.63 kcal/mol) and Mosin B (-45.09 kcal/mol) had superior binding free energies than Pemigatinib (-31.01 kcal/mol). These two lead compounds were subjected to 100 ns molecular dynamics simulation to confirm their interaction behaviour and structural stability. Mosin B and 10-hydroxytrilobacin both surpassed pemigatinib across key structural metrics, establishing them as promising FGFR1 inhibitors with strong binding affinity, pharmacokinetic safety, and dynamic stability, and thus warranting further experimental validation for cholangiocarcinoma therapy.