title: Molecular and Vibrational Dynamics in the Cholesterol-Lowering Agent Lovastatin: Solid-State NMR, Inelastic Neutron Scattering, and Periodic DFT Study.
abstract: Molecular and vibrational dynamics of a widely used cholesterol-lowering agent, lovastatin, have been studied by combining nuclear magnetic resonance relaxation experiments (1H NMR) with inelastic neutron scattering (INS) and periodic density functional theory modeling (plane-wave DFT). According to a complementary experimental study, lovastatin shows no phase transitions down to cryogenic conditions, while a progressive, stepwise activation of several molecular motions is observed below room temperature. The molecular packing and intermolecular forces were analyzed theoretically, supported by a13C NMR study and further correlated with observed molecular dynamics. The NMR relaxation experiments combined with theoretical calculations disclose that molecular dynamics in solid lovastatin is related to methyl group motions and conformational disorder in the methylbutanoate fragment. This is precisely assigned and analyzed quantitatively from both experimental and theoretical perspectives. The neutron vibrational spectroscopy further corroborates that the methyl rotors have a classical nature. In addition to the intramolecular reorientations, the vibrational dynamics was analyzed with an emphasis on the low-wavenumber range. For the first time, the terahertz response of lovastatin was studied by confronting neutron and optical techniques and clearly illustrating their complementarity. The consistent picture of the molecular dynamics is provided, which may support further considerations on alternative drug formulations and the amorphization tendency in this important lipid-lowering drug.
authors.affiliation: Faculty of Physics, Adam Mickiewicz University , Umultowska 85, 61-614, Poznan, Poland.|Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research , 141980, Dubna, Russia.
authors.forename: Paweł
authors.initials: P
authors.lastname: Bilski
authors.affiliation: Faculty of Physics, Adam Mickiewicz University , Umultowska 85, 61-614, Poznan, Poland.|Frank Laboratory of Neutron Physics, Joint Institute for Nuclear Research , 141980, Dubna, Russia.
authors.forename: Kacper
authors.initials: K
authors.lastname: Drużbicki
authors.affiliation: NanoBioMedical Centre, Adam Mickiewicz University , Umultowska 85, 61-614, Poznan, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jenczyk
authors.affiliation: Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences , Grunwaldzka 6, 60-780, Poznan, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Mielcarek
authors.affiliation: Faculty of Physics, Adam Mickiewicz University , Umultowska 85, 61-614, Poznan, Poland.|NanoBioMedical Centre, Adam Mickiewicz University , Umultowska 85, 61-614, Poznan, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Wąsicki
mesh_terms: D002784:Cholesterol / Q000737:chemistry*; D008148:Lovastatin / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D033363:Neutron Diffraction; D011789:Quantum Theory; D014732:Vibration
chemical_list: D002784:Cholesterol; D008148:Lovastatin