title: The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger 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 Schrödinger FEP+ are shown that should encourage others to explore the value of TI in routine Structure-based Drug Design.
authors.affiliation: Department of Chemistry Modeling & Informatics, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. yuan.hu@merck.com.
authors.forename: Yuan
authors.identifier: 0000-0002-1014-6594
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Chemistry Modeling & Informatics, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Sherborne
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Integrative Proteomics Research, BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, NJ, 08854, USA.
authors.forename: Tai-Sung
authors.initials: TS
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Integrative Proteomics Research, BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, NJ, 08854, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Case
authors.affiliation: Department of Chemistry and Chemical Biology, Center for Integrative Proteomics Research, BioMaPS Institute for Quantitative Biology, Rutgers University, Piscataway, NJ, 08854, USA. Darrin.York@rutgers.edu.
authors.forename: Darrin M
authors.initials: DM
authors.lastname: York
authors.affiliation: Department of Chemistry Modeling & Informatics, Merck Research Laboratories, 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. zhuyan.guo@merck.com.
authors.forename: Zhuyan
authors.initials: Z
authors.lastname: Guo
mesh_terms: D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011138:Polytetrafluoroethylene / Q000737:chemistry; D011485:Protein Binding; D011522:Protons; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011522:Protons; D011138:Polytetrafluoroethylene
keywords: Free energy calculation; Free energy perturbation; Protein–ligand binding affinity; Protonation; Tautomerization; Thermodynamic integration