Journal of Computer-Aided Molecular Design

, Volume 30, Issue 7, pp 533–539

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

Article

DOI: 10.1007/s10822-016-9920-5

Cite this article as:
Hu, Y., Sherborne, B., Lee, TS. et al. J Comput Aided Mol Des (2016) 30: 533. doi:10.1007/s10822-016-9920-5

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

Protonation Tautomerization Free energy calculation Thermodynamic integration Free energy perturbation Protein–ligand binding affinity 

Abbreviations

TI

Thermodynamic integration

FEP

Free energy perturbation

MM-GBSA

Molecular mechanics-generalized born surface area

MM-PBSA

Molecular mechanics-Poisson Boltzmann surface area

LIE

Linear interaction energy

MCSS

Maximum common substructure search

FEW

Free-energy workflows

SBDD

Structure-based drug design

MD

Molecular dynamics

Supplementary material

10822_2016_9920_MOESM1_ESM.docx (1.9 mb)
Supplementary material 1 (DOCX 1922 kb)

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Chemistry Modeling & InformaticsMerck Research LaboratoriesKenilworthUSA
  2. 2.Department of Chemistry and Chemical Biology, Center for Integrative Proteomics Research, BioMaPS Institute for Quantitative BiologyRutgers UniversityPiscatawayUSA

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