Ligand based 3D-QSAR model, pharmacophore, molecular docking and ADME to identify potential fibroblast growth factor receptor 1 inhibitors

Abstract

The FGF/FGFR system may affect tumor cells and stromal microenvironment through autocrine and paracrine stimulation, thereby significantly promoting oncogene transformation and tumor growth. Abnormal expression of FGFR1 in cells is considered to be the main cause of tumorigenesis and a potential target for the treatment of cancer. In this study, a combination of structure-based drug carriers and molecular docking-based virtual screening was used to screen new potential FGFR1 inhibitors. Forty eight known inhibitors were collected to establish 3 D-QSAR models and pharmacophore models, investigate the relationship between the activity and conformation of compounds, and verify the efficiency of pharmacophore. In Accelrys Discovery Studio 2016, the ZINC database was filtered by Lipinski's Rule of Five and SMART's filtration. Then, Hypo01 was used for virtual screening of ZINC database. Compounds with predicted activity values less than 1 μM were molecularly docked with FGFR1 protein crystals, the docking results were observed, and the interaction between compounds and targets was studied. The absorption, distribution, metabolism and excretion (ADME) and toxicity of potential inhibitors were studied, and a compound with new structural scaffolds were obtained. It could be further studied to explore their better therapeutic effects.

Communicated by Ramaswamy H. Sarma

Keywords:

• FGFR1
• inhibitor
• QSAR
• molecular docking
• ADME
• pharmacophore

Acknowledgements

Not applicable.

Disclosure statement

The authors declare no conflict of interest.

Authors’ contributions

LH and ZZT conceived and designed the experiments; LH, XLF, HXW and BT performed the experiments; LH, YRX, ZQZ and CXZ analyzed the data; YJW, HC, XLW, HPY, ZS and TLB contributed analysis tools; LH and ZZT wrote the paper. ZZT are the leaders of the project, guiding the experimental design, data analysis, paper writing and revision. All authors read and approved the final manuscript.

Declarations

Availability of data and materials

The datasets and materials used during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by Applied Basic Research Program of Sichuan Province Sichuan (No. 2019YJ0549), Sichuan Science and Technology Department Seedling engineering program (No. 201958), Sichuan Science and Technology program (No. 2019YFG0154).