Design, synthesis and biological evaluation of novel diaminopyrimidine derivatives as covalent fibroblast growth factor receptor 4 inhibitors

Wei, Wei; Li, Yaxin; Peng, Chuang; Yang, Leifu; Mo, Shanyan; Yan, Xinlong; Hu, Liming

doi:10.1016/j.rechem.2023.100893

Cited by 1 publication

(3 citation statements)

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“…Previously reported active compounds having affinity to FGFR4 with IC 50 ≤100nM were collected in one database entitled with FGFR4 inhibitors [3,9,18,19] . These compounds were prepared using Molecular Operating Environment (MOE) version 2019.01 software through three steps which are washing, partial charge calculation and energy minimization using force field MMFF94x with the default gradient 0.1 RMS kcal/(mol.Å).…”

Section: Methodology 21 Pharmacophore 211 Compounds Preparationmentioning

confidence: 99%

“…The binding pocket residues of FGFR4 protein were defined based on the previously reported binding mode of FGF401 (a potent FGFR4 inhibitor) [3,9,18] . In order to assess the reliability and robustness of our docking algorithm, the minimized form of FGF401 was first docked into the binding pocket of FGFR4 protein using different replacement, refinement methods, scoring functions in order to reach the optimum docking algorithm.…”

Section: Molecular Dockingmentioning

confidence: 99%

“…The fibroblast growth factor receptor 4 (FGFR4) is a transmembrane receptor protein that plays a critical role in various cellular processes, including cell growth, differentiation, and survival. Dysregulation of FGFR4 has been implicated in the development and progression of several types of cancer, including breast, liver, lung, and prostate cancer [8,9] .…”

Section: Introductionmentioning

confidence: 99%

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Virtual Screening, Molecular Dynamics, MM-PBSA and In-silico Studies in Search of Potent Novel Fibroblast Growth Factor Receptors 4 Inhibitor

H Fayek,

M Rashad

2024

J Mod Biol Drug Discov

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Objective: The objective of this study was to design a virtual screening (VS) protocol for identifying potential fibroblast growth factor receptor 4 (FGFR4) inhibitors from the commercially available Specs database. This was based on an experimental model of FGFR4 bound to the potent inhibitor FGF401 (PDB: 7VJL), with the aim of discovering novel compounds with therapeutic potential for various tumor types. Methods: The study comprised two main parts. Firstly, a ligand-based pharmacophore model was constructed using known potent FGFR4 inhibitors to discriminate between actives and decoys. Secondly, docking studies of the identified actives were conducted within the binding pocket of the FGFR4 experimental model. This aimed to assess the ability of the compounds to overlay on the reference inhibitor and interact similarly within the binding site. The virtual screening protocol was then applied to the Specs database to identify potential FGFR4 inhibitors. Results: The ligand-based pharmacophore model exhibited promising discrimination capabilities, achieving a true positive percentage of 100% and a false positive percentage of 7%. Docking studies revealed that the selected compounds overlaid well with the reference inhibitor and exhibited interactions within the FGFR4 binding pocket. Through the virtual screening of the Specs database, compound A emerged as the most suitable candidate. Molecular dynamics simulation and Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) calculations further supported the efficacy of compound A as a FGFR4 inhibitor. Additionally, compound A demonstrated favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, along with adherence to Lipinski’s rule of 5, enhancing its potential as a lead compound. Conclusion: In conclusion, compound A emerged as a promising selective FGFR4 inhibitor with potential for therapeutic use in various cancers. Further in vitro experiments and animal cancer model studies are warranted to validate its efficacy. The study highlights the effectiveness of the proposed virtual screening protocol in identifying novel FGFR4 inhibitors, offering a promising avenue for future drug discovery efforts in oncology.

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Section: Methodology 21 Pharmacophore 211 Compounds Preparationmentioning

confidence: 99%

Section: Molecular Dockingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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