Fibroblast growth factor 2 is a druggable target against glioblastoma: A computational investigation
Rabeea Siddique1,2, Syed Ainul Abideen3, Ghulam Nabi4
1Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou Uiversity, Zhengzhou, China.
Abstract:
Fibroblast growth factor 2 (FGF2) is a key player in cancer and tissue homeostasis and regulates renewal of several stem cell types. The FGF2 role in malignant glioma is proven and tagged FGF2, a novel druggable target, is used for developing potent drugs against glioblastoma. In this study, Asinex 51412372, Asinex 51217461, and Asinex 51216586 were filtered to show the best binding affinity for FGF2 with binding energy scores of -8.3 kcal/mol, -8.2 kcal/mol, and -7.8 kcal/mol, respectively. The compounds showed chemical interactions with several vital residues of FGF2 along the compound length. The noticeable residues that interacted with the compounds were Arg15, Asp23, Arg63, and Gln105. In dynamic investigation in solution, the FGF2 reported unstable dynamics in the first 100 ns and gained structural equilibrium in the second phase of 100 ns. The maximum root mean square deviation (RMSD) value touched by the systems is 3 Å. Similarly, the residue flexibility of FGF2 in the presence of compounds was within a stable range and is compact along the simulation time length. The compounds showed robust atomic-level stable energies with FGF2, which are dominated by both van der Waals and electrostatic interactions. The net binding energy of systems varies between -40 kcal/mol and -86 kcal/mol, suggesting the formation of strong intermolecular docked complexes. The drug-likeness and pharmacokinetic properties also pointed toward good structures that are not toxic, have high gastric absorption, showed good distribution, and readily excreted from the body. In summary, the predicted compounds in this study might be ideal hits that might be further optimized for structure and activity during experimental studies.
Insights
Novel compounds show strong binding affinity to Fibroblast Growth Factor 2 (FGF2), a target for glioblastoma drug development. These molecules exhibit favorable drug-like properties, suggesting potential for new cancer therapies.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- Fibroblast Growth Factor 2 (FGF2) is crucial in cancer and tissue homeostasis, regulating stem cell renewal.
- FGF2 plays a significant role in malignant glioma, presenting it as a druggable target for glioblastoma therapies.
Purpose of the Study:
- To identify novel compounds with high binding affinity to FGF2 for glioblastoma treatment.
- To evaluate the binding interactions, dynamics, and pharmacokinetic properties of potential FGF2 inhibitors.
Main Methods:
- In silico screening of Asinex compounds (51412372, 51217461, 51216586) for FGF2 binding affinity.
- Molecular dynamics simulations to assess FGF2-compound interactions and stability.
- Analysis of drug-likeness and pharmacokinetic properties.
Main Results:
- Three Asinex compounds demonstrated significant binding affinity to FGF2, with binding energies up to -8.3 kcal/mol.
- Compounds formed stable interactions with key FGF2 residues (Arg15, Asp23, Arg63, Gln105).
- Molecular dynamics revealed stable FGF2-compound complexes with strong van der Waals and electrostatic interactions, and favorable drug-like and pharmacokinetic profiles.
Conclusions:
- The identified compounds are promising hits for FGF2 inhibition in glioblastoma.
- Further experimental optimization of these compounds is warranted for therapeutic development.
