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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library

Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library

Published on: September 30, 2019

Identification and characterization of binding thermodynamics and kinetics of inhibitors targeting FGFR1 via

Subhasmita Mahapatra¹, Parimal Kar¹

¹Department of Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Khandwa Road, Indore 453552, Madhya Pradesh, India. phd2101271009@iiti.ac.in.

Physical Chemistry Chemical Physics : PCCP

|April 30, 2025

Abstract:

Fibroblast growth factor receptor1 (FGFR1) kinase has a crucial role in cell proliferation, migration, and differentiation. Any imbalance in its level can cause cancer and many other illnesses. Despite the availability of numerous treatments, cytotoxicity, selectivity, and drug resistance issues demand the development of new FGFR1 inhibitors. Herein, we performed a high-throughput virtual screening of 54 624 compounds from NPASS and HMDB databases using the Schrodinger software suite. Compounds with a docking score cutoff of -11.0 kcal mol^-1 were further screened for ADMET properties. Following the all-atom molecular dynamics simulation of selected molecules in replica, the binding free energy was calculated using the molecular mechanics Poisson Boltzmann surface area (MM-PBSA) scheme. We obtained two compounds, namely, bevantolol and 3-hydroxy glabrol, which exhibited higher binding affinities than the control drug ponatinib. Bevantolol was further optimized via virtual screening and simulation studies of its 100 structural analogues to obtain the best analogue. Subsequently, we investigated the binding thermodynamics and kinetics of the best analogue molecule via ligand Gaussian accelerated molecular dynamics (LiGaMD) simulation, performing independent replica runs of 4 μs each. The 1D and 2D potential of mean force and Kramer's rate theory determined the kinetic rate constants (k_on/k_off) associated with the FGFR1 complex. The binding constant was estimated to be 7.4 ± 0.27 nM, which was similar to the type II tyrosine kinase inhibitor ponatinib. Overall, this study highlights the dynamics of FGFR1-ligand interaction while proposing bevantolol and its analogue molecule ANLG-2 as promising drug candidates for FGFR1 therapeutic intervention.

Insights

Researchers identified novel Fibroblast Growth Factor Receptor 1 (FGFR1) inhibitors, bevantolol and ANLG-2, through virtual screening. These compounds show promising binding affinities and kinetics, offering potential new therapies for FGFR1-related diseases.

Area of Science:

Computational chemistry and drug discovery
Molecular modeling and simulation
Pharmacology and medicinal chemistry

Background:

Fibroblast Growth Factor Receptor 1 (FGFR1) kinase is vital for cell functions; its dysregulation is linked to cancer and other diseases.
Existing FGFR1 inhibitors face challenges including cytotoxicity, poor selectivity, and drug resistance, necessitating novel therapeutic agents.
Targeting FGFR1 remains a critical area for developing effective cancer treatments.

Purpose of the Study:

To identify novel, potent, and selective small-molecule inhibitors of FGFR1 kinase.
To computationally screen large compound libraries for potential FGFR1-targeting drug candidates.
To characterize the binding interactions and thermodynamic/kinetic properties of lead compounds.

Main Methods:

High-throughput virtual screening of over 54,000 compounds using Schrodinger software.
Docking, ADMET property prediction, and all-atom molecular dynamics simulations (MM-PBSA).
Ligand Gaussian accelerated molecular dynamics (LiGaMD) simulations to determine binding kinetics and thermodynamics.

Main Results:

Identified bevantolol and 3-hydroxy glabrol with superior binding affinities compared to ponatinib.
Optimized bevantolol through analogue screening, yielding a lead compound ANLG-2.
ANLG-2 demonstrated a binding constant of 7.4 ± 0.27 nM, comparable to ponatinib, with detailed kinetic analysis.

Conclusions:

Bevantolol and its analogue ANLG-2 are promising drug candidates for FGFR1-targeted therapies.
The study elucidates FGFR1-ligand interaction dynamics, providing a foundation for further drug development.
These findings offer a potential new avenue for treating FGFR1-associated pathologies.

Read full analysis

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