Modeling MEK4 Kinase Inhibitors through Perturbed Electrostatic Potential Charges
Rama K Mishra1,2, Kristine K Deibler3, Matthew R Clutter4,5
1Center for Molecular Innovation and Drug Discovery , Northwestern University , 2145 Sheridan Road , Evanston , Illinois 60208 , United States.
Journal of Chemical Information and Modeling
|October 1, 2019
Summary
Researchers developed a robust quantitative structure-activity relationship (QSAR) model to discover novel mitogen-activated protein kinase kinase 4 (MEK4) inhibitors, crucial for targeting prostate cancer metastasis.
Area of Science:
- Oncology
- Medicinal Chemistry
- Computational Biology
Background:
- Mitogen-activated protein kinase kinase 4 (MEK4) is overexpressed in advanced prostate cancer, promoting metastasis.
- Pharmacological validation of MEK4 as an oncology target is hindered by the lack of selective chemical probes.
- Advances in high-throughput screening enable the discovery of selective chemical entities.
Purpose of the Study:
- To develop a highly predictive, non-alignment-based quantitative structure-activity relationship (QSAR) model for MEK4 inhibitors.
- To address limitations of traditional structure-based QSAR modeling with diverse compound sets.
- To facilitate the discovery of novel MEK4-targeting oncology drugs.
Main Methods:
- Computed electrostatic potential (ESP) charges using density functional theory (DFT) for ligands and hinge residues.
- Generated novel descriptors from charge density perturbations of donor and acceptor atoms.
- Developed a robust QSAR model using a diverse dataset of 84 MEK4 inhibitors.
Main Results:
- A highly predictive, non-alignment-based QSAR model was successfully built.
- The model effectively modeled a diverse set of 84 MEK4 inhibitors.
- Novel descriptors derived from charge density perturbations proved valuable for QSAR modeling.
Conclusions:
- The developed QSAR model offers a robust platform for identifying novel MEK4 inhibitors.
- This approach overcomes challenges associated with modeling diverse chemical structures.
- The findings pave the way for the pharmacological validation of MEK4 as an oncology target.
