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A Novel In Vitro Wound Healing Assay to Evaluate Cell Migration
Published on: March 17, 2018
Exploring STAT3 stimulatory potential of novel wound healing molecules by virtual screening and molecular dynamics
Subodh Kumar1, Somya Chaaudhary1, Prateek Paul1
1Stem Cell & Tissue Engineering Research Group, Institute of Nuclear Medicine & Allied Sciences (INMAS), Defence Research and Development Organisation (DRDO), Delhi, India.
Abstract:
STAT3 signaling is a major intrinsic pathway for cell proliferation owing to its frequent activation in injured tissues. Various STAT3-regulated genes encode cytokines and growth factors, the receptors of which in turn activate the same STAT3 pathways, thereby regulating cell proliferation. In present study, we aimed to analyze several compounds for their wound healing and tissue repair potential by computer-aided virtual screening and Molecular dynamics (MD) simulation. Based on literature studies, a total of 36 drug molecules were selected having critical functions in wound healing and tissue repair. The pharmacological features (ADME and toxicity) of these molecules were predicted to find lead molecules among them. Further, a comparative study was performed to screen binding efficiency of STAT3 with many conventional wound healers by molecular docking. Among all, W6S, Strychnin, Prednisone and N-(6-(4-(3-(4-((4-Methylpiperazin-1-yl) methyl)-3- (trifluoromethyl)phenyl)ureido)phenoxy)pyrimidin-4-yl)cyclopropanecarboxamide showed best docking with STAT3 protein. The calculated binding energy of these molecules with STAT3 was found to be -8.9 Kca/mol for N-(6-(4-(3-(4-((4-Methylpiperazin-1-yl) methyl)-3-(trifluoromethyl) phenyl)ureido)phenoxy)pyrimidin-4-yl)cyclopropanecarboxamide, -8.7 Kcal/mol for W6S, -8.5 Kcal/mol for Strychnine and -8.4 Kcal/mol for Prednisone . The result was reconsidered for MD simulation. The simulation result showed stable binding of the ligand with STAT3 protein for 100 ns. These compounds showed better interaction potential with STAT3 was compared to known tissue repair molecules. Our data paves way for further exploration of these molecules as novel cell proliferators to be tested in various types of wound and tissue injuries.Communicated by Ramaswamy H. Sarma.
Insights
This study identifies novel compounds that effectively bind to STAT3, a key pathway in cell proliferation and tissue repair. These findings suggest potential new treatments for wound healing and tissue regeneration.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Biology
Background:
- Signal transducer and activator of transcription 3 (STAT3) signaling is crucial for cell proliferation, particularly in injured tissues.
- STAT3 activation is frequently observed in wound healing, regulating genes involved in tissue repair.
- Understanding STAT3's role offers therapeutic targets for enhancing wound healing and tissue regeneration.
Purpose of the Study:
- To identify novel compounds with wound healing and tissue repair potential.
- To evaluate the binding efficiency of selected drug molecules with the STAT3 protein.
- To investigate the therapeutic prospects of these compounds through computational methods.
Main Methods:
- Virtual screening of 36 drug molecules with known wound healing functions.
- Prediction of ADME (absorption, distribution, metabolism, and excretion) and toxicity profiles.
- Molecular docking and molecular dynamics (MD) simulations to assess STAT3 binding affinity and stability.
Main Results:
- Four compounds, including N-(6-(4-(3-(4-((4-Methylpiperazin-1-yl) methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)pyrimidin-4-yl)cyclopropanecarboxamide, W6S, Strychnine, and Prednisone, showed significant docking scores with STAT3.
- Calculated binding energies ranged from -8.4 to -8.9 Kcal/mol, indicating strong interactions.
- MD simulations confirmed stable binding of these compounds with STAT3 over 100 ns.
Conclusions:
- The identified compounds exhibit promising interaction potential with STAT3 compared to conventional wound healers.
- These molecules represent potential novel cell proliferators for therapeutic applications in wound and tissue injuries.
- Further in vivo and in vitro studies are warranted to validate their efficacy in wound healing and tissue repair.
