title: Interpreting Thermodynamic Profiles of Aminoadamantane Compounds Inhibiting the M2 Proton Channel of Influenza A by Free Energy Calculations.
abstract: The development of novel anti-influenza drugs is of great importance because of the capability of influenza viruses to occasionally cross interspecies barriers and to rapidly mutate. One class of anti-influenza agents, aminoadamantanes, including the drugs amantadine and rimantadine now widely abandoned due to virus resistance, bind to and block the pore of the transmembrane domain of the M2 proton channel (M2TM) of influenza A. Here, we present one of the still rare studies that interprets thermodynamic profiles from isothermal titration calorimetry (ITC) experiments in terms of individual energy contributions to binding, calculated by the computationally inexpensive implicit solvent/implicit membrane molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) approach, for aminoadamantane compounds binding to M2TM of the avian "Weybridge" strain. For all eight pairs of aminoadamantane compounds considered, the trend of the predicted relative binding free energies and their individual components, effective binding energies and changes in the configurational entropy, agrees with experimental measures (ΔΔG, ΔΔH, TΔΔS) in 88, 88, and 50% of the cases. In addition, information yielded by the MM-PBSA approach about determinants of binding goes beyond that available in component quantities (ΔH, ΔS) from ITC measurements. We demonstrate how one can make use of such information to link thermodynamic profiles from ITC with structural causes on the ligand side and, ultimately, to guide decision making in lead optimization in a prospective manner, which results in an aminoadamantane derivative with improved binding affinity against M2TM(Weybridge).
authors.affiliation: Mathematisch-Naturwissenschaftliche Fakultät, Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Homeyer
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771 Athens, Greece.
authors.forename: Harris
authors.initials: H
authors.lastname: Ioannidis
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Eberhard-Karls-Universität Tübingen , 72076 Tübingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Kolarov
authors.affiliation: Institut für Physikalische und Theoretische Chemie, Eberhard-Karls-Universität Tübingen , 72076 Tübingen, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Gauglitz
authors.affiliation: Demokritos, National Center for Scientific Research , 15310 Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Zikos
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens , 15771 Athens, Greece.
authors.forename: Antonios
authors.initials: A
authors.lastname: Kolocouris
authors.affiliation: Mathematisch-Naturwissenschaftliche Fakultät, Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gohlke
mesh_terms: D000547:Amantadine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001059:Apoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D004134:Dimyristoylphosphatidylcholine / Q000378:metabolism; D015195:Drug Design; D006863:Hydrogen-Ion Concentration; D009980:Influenza A virus / Q000187:drug effects; D008024:Ligands; D008051:Lipid Bilayers / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011522:Protons; D013816:Thermodynamics; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001059:Apoproteins; D008024:Ligands; D008051:Lipid Bilayers; D008565:Membrane Proteins; D011522:Protons; D014764:Viral Proteins; D000547:Amantadine; D004134:Dimyristoylphosphatidylcholine