Computational insights into the binding of IN17 inhibitors to MELK

J Mol Model. 2019 May 8;25(6):151. doi: 10.1007/s00894-019-4036-1.

Abstract

The protein kinase MELK is an important kinase in cell signaling and has shown to be a promising anti-cancer target. Recent work has resulted in a novel small molecule scaffold targeting MELK, IN17. However, there has been little structural information or physical understanding of MELK-IN17 interactions. Using Tinker-OpenMM on GPUs, we have performed free energy simulations on MELK binding with IN17 and 11 derivatives. This series of studies provides structural insights into how substitution on IN17 leads to differences in complex structure and binding thermodynamics. In addition, this study serves as an assessment of the current capabilities of the AMOEBA forcefield, accelerated by GPU computing, to serve as a molecular-dynamics-based free energy simulation platform for lead optimization.

Keywords: Free energy calculation; Kinase inhibitor; MELK; Molecular dynamics.

MeSH terms

  • Biophysical Phenomena
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Isomerism
  • Models, Molecular*
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / chemistry*
  • Quantitative Structure-Activity Relationship*
  • Solvents

Substances

  • Indoles
  • Protein Kinase Inhibitors
  • Solvents
  • MELK protein, human
  • Protein Serine-Threonine Kinases
  • nintedanib