Identification of potential drug molecules against fibroblast growth factor receptor 3 (FGFR3) by multi-stage computational-biophysics correlate

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 angstrom. 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.