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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Free energy perturbation
Molecular mechanics-generalized born surface area
Molecular mechanics-Poisson Boltzmann surface area
Linear interaction energy
Maximum common substructure search
Structure-based drug design
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We are grateful to Merck Research Laboratories (MRL) Postdoctoral Research Fellows Program for financial support provided by a fellowship (Y. H.). We thank the AMBER FEW developers Nadine Homeyer and Holger Gohlke for valuable help and discussions in building the workflows. We thank the High Performance Computing (HPC) support at Merck.
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Hu, Y., Sherborne, B., Lee, TS. et al. The importance of protonation and tautomerization in relative binding affinity prediction: a comparison of AMBER TI and Schrödinger FEP. J Comput Aided Mol Des 30, 533–539 (2016). https://doi.org/10.1007/s10822-016-9920-5