The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP

J Comput Aided Mol Des. 2016 Jul;30(7):533-9. doi: 10.1007/s10822-016-9920-5. Epub 2016 Aug 1.

Abstract

In drug discovery, protonation states and tautomerization are easily overlooked. Through a Merck-Rutgers collaboration, this paper re-examined the initial settings and preparations for the Thermodynamic Integration (TI) calculation in AMBER Free-Energy Workflows, demonstrating the value of careful consideration of ligand protonation and tautomer state. Finally, promising results comparing AMBER TI and Schrödinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.

Keywords: Free energy calculation; Free energy perturbation; Protein–ligand binding affinity; Protonation; Tautomerization; Thermodynamic integration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Design*
  • Drug Discovery*
  • Humans
  • Ligands
  • Models, Molecular
  • Polytetrafluoroethylene / chemistry
  • Protein Binding
  • Protons*
  • Thermodynamics

Substances

  • Ligands
  • Protons
  • Polytetrafluoroethylene