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Updated: Jul 9, 2025
Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
Published on: September 30, 2019
Identification of potential drug molecules against fibroblast growth factor receptor 3 (FGFR3) by multi-stage
Sajjad Ahmad1,2,3, Taghreed N Almanaa4, Saifullah Khan5
1Department of Health and Biological Sciences, Abasyn University, Peshawar, Pakistan.
Abstract:
The fibroblast growth factor receptor 3 (FGFR3) is warranted as a promising therapeutic target in bladder cancer as it is described in 75% of papillary bladder tumors. Considering this, the present study was conducted to use different approaches of computer-aided drug discovery (CADD) to identify the best binding compounds against the active pocket of FGFR3. Compared to control pyrimidine derivative, the study identified three promising lead structures; BDC_24037121, BDC_21200852, and BDC_21206757 with binding energy value of -14.80 kcal/mol, -12.22 kcal/mol, and -11.67 kcal/mol, respectively. The control molecule binding energy score was -9.85 kcal/mol. The compounds achieved deep pocket binding and produced balanced interactions of hydrogen bonds and van der Waals. The FGFR3 enzyme residues such as Leu478, Lys508, Glu556, Asn562, Asn622, and Asp635. The molecular dynamic (MD) simulation studies additionally validated the docked conformation stability with respect to FGFR3 with a mean root mean square deviation (RMSD) value of < 3 Å. The root mean square fluctuation (RMSF) complements the complexes structural stability and the residues showed less fluctuation in the presence of compounds. The Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods revalidated compounds better binding and highlighted van der Waals energy to dominate the overall net energy. The docked stability was additionally confirmed by WaterSwap and AMBER normal mode entropy energy analyses. In a nutshell, the compounds shortlisted in this study are promising in term of theoretical binding affinity for FGFR3 but experimental validation is needed.Communicated by Ramaswamy H. Sarma.
Insights
Researchers identified novel compounds targeting fibroblast growth factor receptor 3 (FGFR3) in bladder cancer using computer-aided drug discovery. These compounds show strong theoretical binding affinity, warranting experimental validation for therapeutic development.
Area of Science:
- Computational chemistry and molecular modeling
- Oncology and cancer therapeutics
- Pharmacology and drug discovery
Background:
- Fibroblast growth factor receptor 3 (FGFR3) is a significant therapeutic target in bladder cancer, implicated in 75% of papillary tumors.
- Effective therapeutic strategies are needed to target FGFR3 in bladder cancer treatment.
Purpose of the Study:
- To identify potent small molecules targeting the active pocket of FGFR3 using computer-aided drug discovery (CADD).
- To evaluate the binding affinity and stability of potential drug candidates against FGFR3.
Main Methods:
- Employed various CADD approaches, including molecular docking and simulations.
- Utilized molecular dynamics (MD) simulations, MM/PBSA, MM/GBSA, WaterSwap, and AMBER normal mode entropy analyses.
- Assessed binding energy, interactions with FGFR3 residues (e.g., Leu478, Lys508), and conformational stability (RMSD, RMSF).
Main Results:
- Identified three lead compounds (BDC_24037121, BDC_21200852, BDC_21206757) with superior binding energies (-14.80, -12.22, -11.67 kcal/mol) compared to a control.
- Compounds demonstrated deep pocket binding with favorable hydrogen bond and van der Waals interactions.
- MD simulations and energy revalidation confirmed the stability and strong binding of the identified compounds.
Conclusions:
- The identified compounds exhibit promising theoretical binding affinity for FGFR3.
- These molecules represent potential candidates for further development as FGFR3 inhibitors in bladder cancer.
- Experimental validation is crucial to confirm the therapeutic efficacy of these compounds.
