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Molecular dynamics simulations and in silico peptide ligand screening of the Elk-1 ETS domain
Abrar Hussain1, Peter E Shaw, Jonathan D Hirst
1School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK. jonathan.hirst@nottingham.ac.uk.
Background:
The Elk-1 transcription factor is a member of a group of proteins called ternary complex factors, which serve as a paradigm for gene regulation in response to extracellular signals. Its deregulation has been linked to multiple human diseases including the development of tumours. The work herein aims to inform the design of potential peptidomimetic compounds that can inhibit the formation of the Elk-1 dimer, which is key to Elk-1 stability. We have conducted molecular dynamics simulations of the Elk-1 ETS domain followed by virtual screening.
Results:
We show the ETS dimerisation site undergoes conformational reorganisation at the α1β1 loop. Through exhaustive screening of di- and tri-peptide libraries against a collection of ETS domain conformations representing the dynamics of the loop, we identified a series of potential binders for the Elk-1 dimer interface. The di-peptides showed no particular preference toward the binding site; however, the tri-peptides made specific interactions with residues: Glu17, Gln18 and Arg49 that are pivotal to the dimer interface.
Conclusions:
We have shown molecular dynamics simulations can be combined with virtual peptide screening to obtain an exhaustive docking protocol that incorporates dynamic fluctuations in a receptor. Based on our findings, we suggest experimental binding studies to be performed on the 12 SILE ranked tri-peptides as possible compounds for the design of inhibitors of Elk-1 dimerisation. It would also be reasonable to consider the score-ranked tri-peptides as a comparative test to establish whether peptide size is a determinant factor of binding to the ETS domain.
Insights
Researchers identified specific tri-peptides that bind to the Elk-1 dimer interface, offering potential for new drugs targeting diseases linked to Elk-1 deregulation. These findings guide the design of Elk-1 dimerisation inhibitors.
Area of Science:
- Molecular biology
- Computational chemistry
- Drug discovery
Background:
- Elk-1 is a transcription factor involved in gene regulation and linked to diseases like cancer.
- Elk-1 dimer formation is crucial for its stability and function.
- Targeting Elk-1 dimerisation is a potential therapeutic strategy.
Purpose of the Study:
- To identify compounds that inhibit Elk-1 dimer formation.
- To inform the design of peptidomimetic inhibitors for Elk-1.
Main Methods:
- Molecular dynamics simulations of the Elk-1 ETS domain.
- Virtual screening of di- and tri-peptide libraries.
- Analysis of peptide interactions with the Elk-1 dimer interface.
Main Results:
- The Elk-1 ETS dimerisation site shows conformational flexibility.
- Tri-peptides, but not di-peptides, showed specific binding interactions.
- Key residues (Glu17, Gln18, Arg49) were identified as critical for binding.
Conclusions:
- Combining molecular dynamics and virtual screening provides a robust docking protocol.
- Twelve SILE-ranked tri-peptides are proposed for experimental validation as Elk-1 dimerisation inhibitors.
- Further studies can explore the role of peptide size in binding affinity.
