title: Solvent effect on molecular structure, IR spectra, thermodynamic properties and chemical stability of zoledronic acid: DFT study.
abstract: Zoledronic acid (ZL) has been used widely for treating skeletal diseases because of its high potency in inhibiting bone resorption. A detailed understanding of its physicochemical characteristics may be of great significance in both medicinal chemistry and structural biology for the design of novel bisphosphonates with higher activity. In the present work, the monoclinic (IM) and triclinic (IT) polymorphs of ZL in the gas phase and the aqueous phase were studied by density functional theory (DFT) method at the B3LYP/6-311++G** level. The polarizable continuum model (PCM) was employed to study the solvent effect on structures and properties. The optimized IM and IT conformations in both phases are in reasonable agreement with the experimental structures with the overall mean absolute percent deviation (MAPD%) less than 3.1 %. The presence of intramolecular hydrogen bond within both conformations was identified in the solvent. The IR spectra were simulated and assigned in detail, which agreed well with the experimental data. The intramolecular hydrogen bonding interactions resulted in the shift of vibrational frequencies of hydroxyl to the low band by 12-22 cm(-1) and 24-26 cm(-1) for IM and IT conformations, respectively. Their thermodynamic properties were also calculated based on the harmonic vibrational analysis, including standard heat capacity (C(°)p,m), entropy (S(°)m), and enthalpy (H(°)m). The molecular stability, hydrogen bonding interaction and other electronic properties have been further analyzed by the natural bond orbital (NBO), atoms in molecules (AIM), molecular electrostatic potential (MEP) and frontier molecular orbital (FMO) analysis.
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China. qiuling@jsinm.org.
authors.forename: Ling
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China.
authors.forename: Gaochao
authors.initials: G
authors.lastname: Lv
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Liu
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Nuclear Medicine, Ministry of Health & Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, People's Republic of China. linjianguo@jsinm.org.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Lin
mesh_terms: D050071:Bone Density Conservation Agents / Q000737:chemistry*; D002236:Carbohydrate Conformation; D004164:Diphosphonates / Q000737:chemistry*; D004355:Drug Stability; D005740:Gases / Q000737:chemistry; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D011789:Quantum Theory; D012997:Solvents / Q000737:chemistry; D055672:Static Electricity; D013237:Stereoisomerism; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005740:Gases; D007093:Imidazoles; D012997:Solvents; D014867:Water; D000077211:Zoledronic Acid
keywords: Chemical stability; DFT; Hydrogen bonding; Solvent effect; Zoledronic acid