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

Journal of Computer-Aided Molecular Design vol. 30  p. 533-539  DOI: 10.1007/s10822-016-9920-5
PMID/PMCID: PMC6360336 Published: 2016-07-27 

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

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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.