Synthesis, Electronic Structure Analysis, Pharmacological Evaluation and Molecular Dynamics Investigation of Pyrazole-Triazole Derivative as a Computationally Predicted FGFR-Targeting Candidate Against Glioblastoma

Abstract

Glioblastoma remains a highly invasive brain tumour with limited therapeutic options, highlighting the need for novel FGFR-targeted inhibitors. The objective of the work to explore structural characteristics, electronic behaviour and pharmacological potential of 5-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-1,2,4-triazolidin-3-one (5CPTO) as a in silico-predicted FGFR-binding candidate. A combined computational and experimental strategy was employed, integrating DFT, spectroscopic analysis and computational docking studies to elucidate the structural, spectral and biological attributes of the compound. The optimized geometry showed a nearly planar molecular configuration with preservation of the aromatic framework. Experimental and theoretical FT-IR and NMR data were in close agreement, supporting the assignment of the principal functional groups. Molecular orbital analysis gave a HOMO–LUMO energy gap of 4.757 eV, consistent with moderate electronic stability and intramolecular charge-transfer characteristics. NBO analysis indicated appreciable π-electron delocalization within the molecular framework. MEP mapping and Fukui function analysis located the principal electrophilic and nucleophilic sites, while topological analysis identified covalent as well as weak non-covalent interactions involved in molecular stabilization. ADMET predictions indicated favourable oral bioavailability, low toxicity, and conformity with Lipinski’s drug-likeness criteria. Molecular docking with FGFR4 (PDB ID: 7DTZ) yielded a binding energy of -7.73 kcal/mol, with hydrogen bonds and hydrophobic contacts contributing to ligand recognition at the binding site. During the 100 ns MD simulation, the 5CPTO–FGFR4 complex maintained stable RMSD, RMSF, and radius of gyration profiles. MMPBSA calculations gave favourable binding free-energy values, with van der Waals and hydrophobic interactions making major energetic contributions. These computational findings support the structural stability, electronic characteristics, and FGFR4-binding capability of 5CPTO and provide a basis for its further evaluation through in vitro enzymatic and cell-based studies related to glioblastoma.