Virtual Screening, Molecular Dynamics, MM-PBSA and In-silico Studies in Search of Potent Novel Fibroblast Growth Factor Receptors 4 Inhibitor

Abstract

Objective: The objective of this study was to design a virtual screening (VS) protocol for identifying potential fibroblast growth factor receptor 4 (FGFR4) inhibitors from the commercially available Specs database. This was based on an experimental model of FGFR4 bound to the potent inhibitor FGF401 (PDB: 7VJL), with the aim of discovering novel compounds with therapeutic potential for various tumor types. Methods: The study comprised two main parts. Firstly, a ligand-based pharmacophore model was constructed using known potent FGFR4 inhibitors to discriminate between actives and decoys. Secondly, docking studies of the identified actives were conducted within the binding pocket of the FGFR4 experimental model. This aimed to assess the ability of the compounds to overlay on the reference inhibitor and interact similarly within the binding site. The virtual screening protocol was then applied to the Specs database to identify potential FGFR4 inhibitors. Results: The ligand-based pharmacophore model exhibited promising discrimination capabilities, achieving a true positive percentage of 100% and a false positive percentage of 7%. Docking studies revealed that the selected compounds overlaid well with the reference inhibitor and exhibited interactions within the FGFR4 binding pocket. Through the virtual screening of the Specs database, compound A emerged as the most suitable candidate. Molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculations further supported the efficacy of compound A as a FGFR4 inhibitor. Additionally, compound A demonstrated favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, along with adherence to Lipinski’s rule of 5, enhancing its potential as a lead compound. Conclusion: In conclusion, compound A emerged as a promising selective FGFR4 inhibitor with potential for therapeutic use in various cancers. Further in vitro experiments and animal cancer model studies are warranted to validate its efficacy. The study highlights the effectiveness of the proposed virtual screening protocol in identifying novel FGFR4 inhibitors, offering a promising avenue for future drug discovery efforts in oncology.