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

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 c...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 2016-07, Vol.30 (7), p.533-539
Main Authors: Hu, Yuan, Sherborne, Brad, Lee, Tai-Sung, Case, David A., York, Darrin M., Guo, Zhuyan
Format: Article
Language:English
Subjects:
Animal Anatomy
Binding
Binding sites
CAD
Chemistry
Chemistry and Materials Science
Comparative studies
Computer aided design
Computer Applications in Chemistry
Drug Design
Drug Discovery
Drugs
Histology
Humans
Ligands
Mathematical analysis
Models, Molecular
Morphology
Physical Chemistry
Polytetrafluoroethylene - chemistry
Protein Binding
Protonation
Protons
Schroedinger equation
Tautomers
Thermodynamics
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Summary: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.
ISSN:0920-654X
1573-4951
DOI:10.1007/s10822-016-9920-5