Department of Physics, University of Lucknow, Lucknow 226007, India.
Department of Physics, University of Lucknow, Lucknow 226007, India.
Spectrochim Acta A Mol Biomol Spectrosc. 2018 Oct 5;203:1-12. doi: 10.1016/j.saa.2018.05.074. Epub 2018 May 22.
Febuxostat (FXT) is a urate-lowering drug and xanthine oxidase inhibitor which is used for the treatment of hyperuricemia and gout caused by increased levels of uric acid in the blood (hyperuricemia). The present study aims to provide deeper knowledge of the structural, vibrational spectroscopic and physiochemical properties of FXT based on monomeric and dimeric model with the aid of combination of experimental and computational methods. The conformational analysis of form Q has been done to predict the possible structure of unknown form A. Vibrational spectra of form A and Q has been compared to get an idea of hydrogen bonding interactions of form A. A computational study of FXT has been executed at different level (B3LYP, M06-2X, WB97XD) of theory and 6-31 G (d, p) basis set for dimeric model to elucidate the nature of intermolecular hydrogen bond. The red shift observed in the stretching modes of OH, CO groups and blue shift in stretching mode of CN group in experimental as well as in theoretical spectra explains the involvement of these groups in intermolecular hydrogen bonding. NBO analysis shows that change in electron density (ED) in the lone pair orbital to σ* antibonding orbital (LP1 (N39) → σ* (O3-H38)) with maximum value of E(2) energy confirms the presence of hydrogen bond (N39⋯H38-O3) leading to dimer formation. Study of topological parameters was executed for dimer using Bader's atoms in molecules (AIM) theory predicting the partially covalent nature of hydrogen bonds present in the molecule. The study of molecular electrostatic potential surface (MEPS) map ascertains that the CO, CN group are prone to electrophilic attack and OH group is active towards nucleophilic attack. The lower energy band gap and higher value of softness of dimeric model of FXT indicates its more reactivity, polarisability than monomeric model. The local reactivity descriptors predict the order of reactive sites towards electrophilic, nucleophilic and radical attack. An investigation made to determine the ligand protein interaction of FXT through docking with different molecular targets reveals the inhibitive as well as antibacterial nature of FXT.
非布司他（FXT）是一种尿酸降低药物和黄嘌呤氧化酶抑制剂，用于治疗因血液中尿酸水平升高（高尿酸血症）引起的高尿酸血症和痛风。本研究旨在借助实验和计算方法的结合，提供对 FXT 单体和二聚体模型结构、振动光谱和物理化学性质的更深入了解。已经对形式 Q 进行了构象分析，以预测未知形式 A 的可能结构。比较了形式 A 和 Q 的振动光谱，以了解形式 A 的氢键相互作用。在不同理论水平（B3LYP、M06-2X、WB97XD）和 6-31G（d，p）基组上对 FXT 进行了计算研究，以阐明分子间氢键的性质。在实验和理论光谱中观察到的 OH、CO 基团伸缩模式的红移和 CN 基团伸缩模式的蓝移表明这些基团参与了分子间氢键。NBO 分析表明，孤对轨道（LP1（N39））到 σ*反键轨道的电子密度（ED）变化最大，值为 E（2）能量，证实了氢键（N39⋯H38-O3）的存在，导致二聚体的形成。使用 Bader 的分子中原子（AIM）理论对二聚体执行拓扑参数研究，预测分子中存在部分共价氢键。分子静电势表面（MEPS）图的研究确定 CO、CN 基团容易受到亲电攻击，OH 基团对亲核攻击活性。FXT 二聚体的较低能带隙和较高的软度值表明其比单体模型具有更高的反应性、极化率。局部反应性描述符预测了亲电、亲核和自由基攻击的反应活性位点的顺序。通过与不同分子靶标对接进行的 FXT 配体蛋白相互作用的研究表明了 FXT 的抑制和抗菌性质。
