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

Yuan Hu; Brad Sherborne; Tai Sung Lee; David A. Case; Darrin M. York; Zhuyan Guo

doi:10.1007/s10822-016-9920-5

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

Yuan Hu, Brad Sherborne, Tai Sung Lee, David A. Case, Darrin M. York, Zhuyan Guo

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	533-539
Number of pages	7
Journal	Journal of Computer-Aided Molecular Design
Volume	30
Issue number	7
DOIs	https://doi.org/10.1007/s10822-016-9920-5
State	Published - Jul 1 2016

All Science Journal Classification (ASJC) codes

Drug Discovery
Computer Science Applications
Physical and Theoretical Chemistry

Keywords

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

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10.1007/s10822-016-9920-5

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title = "The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schr{\"o}dinger FEP",

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 Schr{\"o}dinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.",

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T1 - The importance of protonation and tautomerization in relative binding affinity prediction

T2 - a comparison of AMBER TI and Schrödinger FEP

AU - Hu, Yuan

AU - Sherborne, Brad

AU - Lee, Tai Sung

AU - Case, David A.

AU - York, Darrin M.

AU - Guo, Zhuyan

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - Free energy calculation

KW - Free energy perturbation

KW - Protein–ligand binding affinity

KW - Protonation

KW - Tautomerization

KW - Thermodynamic integration

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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