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

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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.

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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

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Acknowledgments

We are grateful to Merck Research Laboratories (MRL) Postdoctoral Research Fellows Program for financial support provided by a fellowship (Y. H.). We thank the AMBER FEW developers Nadine Homeyer and Holger Gohlke for valuable help and discussions in building the workflows. We thank the High Performance Computing (HPC) support at Merck.

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Authors and Affiliations

  1. Department of Chemistry Modeling & Informatics, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    Yuan Hu, Brad Sherborne & Zhuyan Guo

  2. Department of Chemistry and Chemical Biology, Center for Integrative Proteomics Research, BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, NJ, 08854, USA

    Tai-Sung Lee, David A. Case & Darrin M. York

Authors
  1. Yuan Hu
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  2. Brad Sherborne
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  3. Tai-Sung Lee
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  4. David A. Case
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  5. Darrin M. York
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  6. Zhuyan Guo
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Corresponding authors

Correspondence to Yuan Hu, Darrin M. York or Zhuyan Guo.

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Hu, Y., Sherborne, B., Lee, TS. et al. The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP. J Comput Aided Mol Des 30, 533–539 (2016). https://doi.org/10.1007/s10822-016-9920-5

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  • DOI: https://doi.org/10.1007/s10822-016-9920-5

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