Decoding the Conformational Selective Mechanism of FGFR Isoforms: A Comparative Molecular Dynamics Simulation.

Area of Science:

• Molecular biology
• Biochemistry
• Computational chemistry

Background:

• Fibroblast growth factor receptors (FGFRs) regulate cell growth and proliferation.
• FGFR2 gene amplification is linked to gastric and breast cancers.
• Developing selective FGFR2 inhibitors is challenging due to conserved ATP-binding pockets in FGFR isoforms, leading to toxic side effects with pan-FGFR inhibitors.

Purpose of the Study:

• To elucidate the mechanism of selective FGFR2 inhibition by a newly discovered indazole-based compound.
• To provide a structural basis for the design of targeted cancer therapies.

Main Methods:

• Extensive molecular dynamics simulations of apo and inhibitor-bound FGFR2.
• Analyses including Markov state models, principal component analysis, cross-correlation matrix, binding free energy calculations, and community network analysis.

Main Results:

• Inhibitor binding promotes a switch of the FGFR2 phosphate-binding loop (P-loop) from an open to a closed conformation.
• This conformational change enhances hydrophobic interactions between FGFR2 and the inhibitor, contributing to selectivity.
• Key intermediate conformational states, dynamics, and driving forces of the P-loop transition were identified.

Conclusions:

• The study provides a structural understanding of the closed P-loop conformation in FGFR2 inhibition.
• Findings offer insights into designing selective FGFR2 inhibitors for cancer treatment.
• The indazole-based inhibitor demonstrates potential for targeted cancer therapy with reduced toxicity.