Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Aug 21;14(1):19439.
doi: 10.1038/s41598-024-69850-1.

Structure-based drug-development study against fibroblast growth factor receptor 2: molecular docking and Molecular dynamics simulation approaches

Anas Shamsi  1 , Mohd Shahnawaz Khan  2 , Dharmendra Kumar Yadav  3 , Moyad Shahwan  4   5 , Mohammad Furkan  6 , Rizwan Hasan Khan  7
Affiliations

Structure-based drug-development study against fibroblast growth factor receptor 2: molecular docking and Molecular dynamics simulation approaches

Anas Shamsi et al. Sci Rep. .

Erratum in

Abstract

Developing new therapeutic strategies to target specific molecular pathways has become a primary focus in modern drug discovery science. Fibroblast growth factor receptor 2 (FGFR2) is a critical signaling protein involved in various cellular processes and implicated in numerous diseases, including cancer. Existing FGFR2 inhibitors face limitations like drug resistance and specificity issues. In this study, we present an integrated structure-based bioinformatics analysis to explore the potential of FGFR2 inhibitors-like compounds from the PubChem database with the Tanimoto threshold of 80%. We conducted a structure-based virtual screening approach on a dataset comprising 2336 compounds sourced from the PubChem database. Primarily, the selection of promising compounds was based on several criteria, such as drug-likeness, binding affinities, docking scores, and selectivity. Further, we conducted all-atom molecular dynamics (MD) simulations for 200 ns, followed by an essential dynamics analysis. Finally, a promising FGFR2 inhibitor with PubChem CID:507883 (1-[7-(1H-benzimidazol-2-yl)-4-fluoro-1H-indol-3-yl]-2-(4-benzoylpiperazin-1-yl)ethane-1,2-dione) was screened out from the study. This compound indicates a higher potential for inhibiting FGFR2 than the control inhibitor, Zoligratinib. The identified compound, CID:507883 shows >80% structural similarity with Zoligratinib. ADMET analysis showed promising pharmacokinetic potential of the screened compound. Overall, the findings indicate that the compound CID:507883 may have promising potential to serve as a lead candidate against FGFR2 and could be further exploited in therapeutic development.

Keywords: Drug discovery; FGFR2 inhibitors; Fibroblast growth factor receptor 2; Molecular dynamics simulations; Virtual screening.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Interaction plots. (A) Presentation of binding mode of CID:507883 and the reference drug Zoligratinib with FGFR2. (B) Magnified cartoon representation of FGFR2 binding pocket complex with (i) CID:507883 and (ii) Zoligratinib. (C) Surface representation of FGFR2 complex with (i) CID:507883 and (ii) Zoligratinib. CID:507883: green element, Zoligratinib: yellow element. The angle and distance cut-off for hydrogen bonds between donor and acceptor were set to 3.5 Å and 150-180°, respectively.
Figure 2
Figure 2
2D interaction plots of compound (A) CID:507883. (B) Zoligratinib, and (C) Co-crystalized inhibitor EVC toward FGFR2.
Figure 3
Figure 3
Dynamics of FGFR2 upon ligands binding. (A) RMSD plot as a function of time. (B) Backbone RMS fluctuations in FGFR2 upon ligands binding.
Figure 4
Figure 4
(A) Time evolution of radius of gyration (rGyr) values during 200 ns of MD simulation. (B) Solvent Accessible Surface Area (SASA) as a function of time. Black, red, and aqua represent values obtained from FGFR2, FGFR2-CID:507883 and FGFR2-Zoligratinib complexes respectively.
Figure 5
Figure 5
Dynamics of hydrogen bonding. (A) Formation of intramolecular hydrogen bonds within FGFR2 as a function of time. (B) The average number of hydrogen bonds distribution and their probability. Formation of intermolecular hydrogen bonds between FGFR2 and (C) CID:507883 and (D) Zoligratinib. Black, red, and aqua represent the time-evolution of hydrogen bonds formed within FGFR2, FGFR2-CID:507883, and FGFR2-Zoligratinib complexes, respectively.
Figure 6
Figure 6
Two-dimensional projections of PCA trajectories on both eigenvectors showed conformational landscapes of FGFR2 and its complexes with CID:507883 and Zoligratinib.
Figure 7
Figure 7
The free energy landscape plots obtained during 200 ns MD simulation for (A) FGFR2, (B) FGFR2-CID:507883, (C) FGFR2-Zoligratinib. Lower panels showed the structural snapshots of FGFR2, and its docked complexes fetched from the global minima after the simulations.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Klint, P. & Claesson-Welsh, L. Signal transduction by fibroblast growth factor receptors. Front. Biosci.4, D165-177 (1999). - PubMed
    1. Cleaver, O. & Melton, D. A. Endothelial signaling during development. Nat. Med.9, 661–668 (2003). - PubMed
    1. Givol, D. & Yayon, A. Complexity of FGF receptors: genetic basis for structural diversity and functional specificity. FASEB J.6, 3362–3369 (1992). - PubMed
    1. Ornitz, D. M. & Itoh, N. The fibroblast growth factor signaling pathway. WIREs Dev. Biol.4, 215–266 (2015). - PMC - PubMed
    1. Ibrahimi, O. A., Zhang, F., Lang Hrstka, S. C., Mohammadi, M. & Linhardt, R. J. Kinetic model for FGF, FGFR, and proteoglycan signal transduction complex assembly. Biochemistry43, 4724–4730 (2004). - PubMed

MeSH terms

Substances

LinkOut - more resources