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
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.