Abstract
Protonation states of protein residues in ligand binding sites determine the electrostatic potential, which is essential to understand the interactions of the ligand and the protein. The case of aldose reductase is shown as an example. Inhibitors bind to the active site and to the nearby selectivity pocket. The case of two inhibitors, IDD 594 and Fidarestat, is discussed. The binding properties are determined by the protonation states of the protein residues, notably of His 110, and by the protonation state of the ligand, which can change in the case of Fidarestat. In this latter case the change in the charged state of the ligand during binding, from neutral to negative, combines the advantage of strong potency (charged state) and favorable pharmacokinetics (neutral state).
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Acknowledgments
We thank Andre Mitschler and Alexandra Cousido-Siah for their efforts in crystallization and data collection, the SBC staff for their support in data collection; N. Muzet and B. Guillot for electrostatic calculations, and Ossama El-Kabbani for his participation in the Fidarestat project. This work was supported by the Centre National de la Recherché Scientifique (CNRS), by collaborative projects CNRS-CONICET, CNRS-CERC and CNRS-NSF (INT-9815595), by Ecos Sud, by USA Federal funds from the National Cancer Institute (Contract No. NO1-CO-12400) and the National Institutes of Health, by the Institut National de la Santé et de la Recherché Médicale and the Hôpital Universitaire de Strasbourg (H.U.S), and by the Institute for Diabetes Discovery, Inc. through a contract with the CNRS, and in part by the U.S. Department of Energy, Office of Biological and Environmental Research under contract No. W-31-109-ENG-38. EH is a member of Carrera del Investigador, CONICET, Argentina.
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Podjarny, A., Howard, E. (2015). Importance of Protonation States for the Binding of Ligands to Pharmaceutical Targets. In: Scapin, G., Patel, D., Arnold, E. (eds) Multifaceted Roles of Crystallography in Modern Drug Discovery. NATO Science for Peace and Security Series A: Chemistry and Biology. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9719-1_11
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