The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP |
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| Authors: | Yuan Hu Brad Sherborne Tai-Sung Lee David A Case Darrin M York Zhuyan Guo |
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| Institution: | 1.Department of Chemistry Modeling & Informatics,Merck Research Laboratories,Kenilworth,USA;2.Department of Chemistry and Chemical Biology, Center for Integrative Proteomics Research, BioMaPS Institute for Quantitative Biology,Rutgers University,Piscataway,USA |
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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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