title: Assessing the protonation state of drug molecules: the case of aztreonam.
abstract: Herein we examine the viability of physicochemical approaches based on standard computational chemistry tools to characterize the structure and energetics of flexible drug molecules with various titratable sites. We focus on the case of the monobactam antibiotic aztreonam, whose structure and physicochemical properties have been ascribed to several tautomeric forms, although it is still unclear which protonation states are responsible for its biological activity. First, we experimentally determined the pKa values for aztreonam over the pH range 0.8-7.0 using both 1H NMR and 13C NMR spectroscopy. Second, we carried out quantum chemical calculations on snapshots extracted from classical molecular dynamics simulations. Various levels of approximation were used in the energy calculations: ONIOM(HF/3-21G*:AMBER) for geometry relaxation, B3LYP/6-31+G** for electronic and electrostatic solvation energies, and molecular mechanics for attractive dispersion energy. The value of the free energy of solvation of a proton was treated as a parameter and chosen to give the best match between calculated and experimental pKa values for small molecules. Overall, this computational scheme can give satisfactory results in the pKa calculations for drug molecules.
authors.affiliation: Departamento de Química Física y Analítica, Universidad de Oviedo, Julian Clavería 8, 33006 Oviedo (Asturias), Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Díaz
authors.forename: Tomás L
authors.initials: TL
authors.lastname: Sordo
authors.forename: Dimas
authors.initials: D
authors.lastname: Suárez
authors.forename: Rosa
authors.initials: R
authors.lastname: Méndez
authors.forename: Javier Martín
authors.initials: JM
authors.lastname: Villacorta
authors.forename: Luis
authors.initials: L
authors.lastname: Simón
authors.forename: Manuel
authors.initials: M
authors.lastname: Rico
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Jiménez
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001398:Aztreonam / Q000737:chemistry*; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011522:Protons; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D011522:Protons; D001398:Aztreonam