Identification and characterization of binding thermodynamics and kinetics of inhibitors targeting FGFR1 via molecular modelling and ligand Gaussian accelerated molecular dynamics simulations

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.