Identification of novel inhibitors of mitogen-activated protein kinase phosphatase-1 with structure-based virtual screening

J Comput Aided Mol Des. 2011 May;25(5):469-75. doi: 10.1007/s10822-011-9432-2. Epub 2011 May 13.

Abstract

Mitogen-activated protein kinase phosphatase-1 (MKP-1) has proved to be an attractive target for the development of therapeutics for the treatment of cancer. We report the first example for a successful application of the structure-based virtual screening to identify the novel inhibitors of MKP-1. It is shown that the efficiency of virtual screening can be enhanced significantly by the incorporation of a new solvation energy term in the scoring function. The newly found inhibitors have desirable physicochemical properties as a drug candidate and reveal a moderate potency with IC(50) values ranging from 20 to 50 μM. Therefore, they deserve a consideration for further development by structure-activity relationship studies to optimize the inhibitory activities. Structural features relevant to the stabilization of the inhibitors in the active site of MKP-1 are discussed in detail.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Drug Design
  • Drug Evaluation, Preclinical*
  • Dual Specificity Phosphatase 1 / antagonists & inhibitors*
  • Dual Specificity Phosphatase 1 / chemistry*
  • Enzyme Assays
  • Enzyme Inhibitors / chemistry
  • Inhibitory Concentration 50
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / chemistry*
  • Models, Molecular*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Mitogen-Activated Protein Kinase 1
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1