Presentation Title

Identifying Potential Inhibitors for the Enzyme ERK5

Faculty Mentor

Matt Joyner

Start Date

17-11-2018 12:30 PM

End Date

17-11-2018 2:30 PM

Location

CREVELING 85

Session

POSTER 2

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

The enzyme ERK5 is a member of the MAPK family and has been linked to various cellular mechanisms such as proliferation, migration, cell survival, and angiogenesis. The potential involvement of ERK5 in various forms of cancer has led to the emergence of this enzyme as a potential therapeutic drug target. It was hypothesized that, by using virtual screening tools, potential inhibitors of the ERK5 enzyme would be identified. Analysis of the predicted interactions of ligands with important residues in the ERK5 active site would enable further insight into the potential of each compound as an inhibitor. The software AutoDock Vina was used for generating a set of orientations and locations that produced favorable binding of the ligand. A library of approximately 1700 compounds obtained from PubChem database was screened for binding interactions in both the ATP-binding site and the allosteric binding site of the ERK5 enzyme to determine inhibitory potential. The DSX scoring function was then used to re-score the binding interactions to better reflect the best binding pose and affinity of the ligand to the protein. Specific interactions between the ligands and ERK5 residues were visualized in Pymol. In the active site, compounds that showed the strongest potential as ERK5 inhibitors formed hydrogen bonds with the residues Met140, Lys84, and Asp200. In the allosteric site, the best potential inhibitors had hydrogen bonds Asn95, Arg98, and Thr99. From the library of compounds, 37 showed strong inhibitory potential in the ATP-binding site and 35 in the Allosteric binding site. The set of compounds obtained from the virtual screening provides candidates that can potentially be used to inhibit the ERK5 enzyme and discover more about its functions and mechanisms. Testing inhibitory activity of the different compounds in vitro will enable further quantitative evaluation of the screening results.

Summary of research results to be presented

The procedure and methods used in the virtual screening process will be included in the results to show the validity of the project. The docking and scoring process was used with known inhibitors that had previously reported inhibitory activity. The docking of these compounds was used to calibrate future docking analysis and develop criteria for important residues in the binding sites of ERK5. The important ERK5 residues and the important interactions that formed between the ligands with strong inhibitory potential will also be reported. From the, approximately, 1700 compounds that were tested, the 37 that showed strong inhibitory potential through binding in the active site and the 35 that showed similar potential though interactions formed in the allosteric site, will be presented. In addition, certain compounds that were identified were found to have a history of kinase inhibiting activity. This information will also be provided to confirm validity of the findings and show the potential for discovery of compounds of which can inhibit ERK5 that have yet be identified.

This document is currently not available here.

Share

COinS
 
Nov 17th, 12:30 PM Nov 17th, 2:30 PM

Identifying Potential Inhibitors for the Enzyme ERK5

CREVELING 85

The enzyme ERK5 is a member of the MAPK family and has been linked to various cellular mechanisms such as proliferation, migration, cell survival, and angiogenesis. The potential involvement of ERK5 in various forms of cancer has led to the emergence of this enzyme as a potential therapeutic drug target. It was hypothesized that, by using virtual screening tools, potential inhibitors of the ERK5 enzyme would be identified. Analysis of the predicted interactions of ligands with important residues in the ERK5 active site would enable further insight into the potential of each compound as an inhibitor. The software AutoDock Vina was used for generating a set of orientations and locations that produced favorable binding of the ligand. A library of approximately 1700 compounds obtained from PubChem database was screened for binding interactions in both the ATP-binding site and the allosteric binding site of the ERK5 enzyme to determine inhibitory potential. The DSX scoring function was then used to re-score the binding interactions to better reflect the best binding pose and affinity of the ligand to the protein. Specific interactions between the ligands and ERK5 residues were visualized in Pymol. In the active site, compounds that showed the strongest potential as ERK5 inhibitors formed hydrogen bonds with the residues Met140, Lys84, and Asp200. In the allosteric site, the best potential inhibitors had hydrogen bonds Asn95, Arg98, and Thr99. From the library of compounds, 37 showed strong inhibitory potential in the ATP-binding site and 35 in the Allosteric binding site. The set of compounds obtained from the virtual screening provides candidates that can potentially be used to inhibit the ERK5 enzyme and discover more about its functions and mechanisms. Testing inhibitory activity of the different compounds in vitro will enable further quantitative evaluation of the screening results.