Modeling MEK4 Kinase Inhibitors through Perturbed Electrostatic Potential (ESP) Charges

Rama K. Mishra, Kristine K. Deibler, Matthew R. Clutter, Purav Pankaj Vagadia, Matthew O'Connor, Gary E. Schiltz, Raymond Bergan, Karl A. Scheidt

Research output: Contribution to journalArticle

Abstract

MEK4, mitogen-activated protein kinase kinase 4, is overexpressed and induces metastasis in advanced prostate cancer lesions. However, the value of MEK4 as an oncology target has not been pharmacologically validated because selective chemical probes targeting MEK4 have not been developed. With advances in both computer and biological high-throughput screening selective chemical entities can be discovered. Structure-based quantitative structure activity relationship (QSAR) modeling often fails to generate accurate models due to poor alignment of training sets containing highly diverse compounds. Here we describe a highly predictive, non-alignment based robust QSAR model based on a dataset of strikingly diverse MEK4 inhibitors. We computed the electrostatic potential (ESP) charges using DFT formalism of the donor and acceptor atoms of the ligands and hinge residues. Novel descriptors were then generated from the perturbation of the charge densities of the donor and acceptor atoms and were used to model a diverse set of 84 compounds, from which we built a robust predictive model.

Original languageEnglish (US)
JournalJournal of Chemical Information and Modeling
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Electrostatics
activity structure
Phosphotransferases
non-alignment
predictive model
MAP Kinase Kinase 4
Atoms
Oncology
cancer
Hinges
Charge density
Discrete Fourier transforms
Screening
Ligands
Throughput
Proteins
Values

Keywords

  • Charge Perturbation
  • CoMFA
  • DFT
  • ESP Charges
  • EVA
  • HQSAR
  • MEK4
  • MLR

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Mishra, R. K., Deibler, K. K., Clutter, M. R., Vagadia, P. P., O'Connor, M., Schiltz, G. E., ... Scheidt, K. A. (Accepted/In press). Modeling MEK4 Kinase Inhibitors through Perturbed Electrostatic Potential (ESP) Charges. Journal of Chemical Information and Modeling. https://doi.org/10.1021/acs.jcim.9b00490

Modeling MEK4 Kinase Inhibitors through Perturbed Electrostatic Potential (ESP) Charges. / Mishra, Rama K.; Deibler, Kristine K.; Clutter, Matthew R.; Vagadia, Purav Pankaj; O'Connor, Matthew; Schiltz, Gary E.; Bergan, Raymond; Scheidt, Karl A.

In: Journal of Chemical Information and Modeling, 01.01.2019.

Research output: Contribution to journalArticle

Mishra, Rama K. ; Deibler, Kristine K. ; Clutter, Matthew R. ; Vagadia, Purav Pankaj ; O'Connor, Matthew ; Schiltz, Gary E. ; Bergan, Raymond ; Scheidt, Karl A. / Modeling MEK4 Kinase Inhibitors through Perturbed Electrostatic Potential (ESP) Charges. In: Journal of Chemical Information and Modeling. 2019.
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