Department of Pharmaceutical Chemistry, Central Instruments Facility (CIF), R. C. Patel Institute of Pharmaceutical Education and Research, Karwand Naka, Shirpur, Dist: Dhule (MS), 425 405, India.
Analytical Chemistry, Chemometrics and Molecular Modelling (FABI), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussel, Belgium.
J Pharm Biomed Anal. 2020 Feb 5;179:112982. doi: 10.1016/j.jpba.2019.112982. Epub 2019 Nov 15.
The obligatory testing of drug molecules and their impurities to protect users against toxic compounds seems to provide interesting opportunities for new drug discovery. Impurities, which proved to be non-toxic, may be explored for their own therapeutic potential and thus be a part of future drug discovery. The essential role of pharmaceutical analysis can thus be extended to achieve this purpose. The present study examined these objectives by characterizing the major degradation products of zileuton (ZLT), a 5-lipoxygenase (5-LOX) inhibitor being prevalently used to treat asthma. The drug sample was exposed to forced degradation and found susceptible to hydrolysis and oxidative stress. The obtained Forced Degradation Products (FDP's) were resolved using an earlier developed and validated Ultra-High-Pressure Liquid Chromatography Photo-Diode-Array (UHPLC-PDA) protocol. ZLT, along with acid-and alkali-stressed samples, were subjected to Liquid-chromatography Mass-spectrometry Quadrupole Time-of-flight (LC/MS-QTOF) studies. Major degradation products were isolated using Preparative TLC and characterized using Q-TOF and/or Proton nuclear magnetic resonance (HNMR) studies. The information obtained was assembled for structural conformation. Toxicity Prediction using Komputer Assisted Technology (TOPKAT) toxicity analyses indicated some FDP's as non-toxic when compared to ZLT. Hence, these non-toxic impurities may have bio-affinity and can be explored to interact with other therapeutic targets, to assist in drug discovery. The drug molecule and the characterized FDP's were subjected to 3-Dimensional Extra Precision (3D-XP)-molecular docking to explore changes in bio-affinity for the 5-LOX enzyme (PDB Id: 3V99). One FDP was found to have a higher binding affinity than the drug itself, indicating it may be a suitable antiasthmatic. The possibility of being active at other sites cannot be neglected and this is evaluated to a reasonable extent by Prediction of Activity Spectra for Substances (PASS). Besides being antiasthmatic, some FDP's were predicted antineoplastic, antiallergic and inhibitors of Complement Factor-D.
强制检测药物分子及其杂质以保护使用者免受有毒化合物的侵害，这似乎为新药发现提供了有趣的机会。已证明无毒的杂质可探索其自身的治疗潜力，从而成为未来药物发现的一部分。因此，药物分析的重要作用可以扩展到实现这一目标。本研究通过对 5-脂氧合酶（5-LOX）抑制剂齐留通（ZLT）的主要降解产物进行表征来检验这些目标，齐留通被广泛用于治疗哮喘。将药物样品暴露于强制降解条件下，发现其易发生水解和氧化应激。使用先前开发和验证的超高效液相色谱光电二极管阵列（UHPLC-PDA）方案对获得的强制降解产物（FDP）进行了分离。ZLT 以及酸和碱胁迫样品均进行了液相色谱-质谱四极杆飞行时间（LC/MS-QTOF）研究。使用制备型薄层色谱法分离主要降解产物，并使用 Q-TOF 和/或质子核磁共振（HNMR）研究对其进行表征。获得的信息被组合用于结构构象。使用 Komputer Assisted Technology（TOPKAT）毒性分析对毒性预测表明，与 ZLT 相比，一些 FDP 无毒。因此，这些无毒杂质可能具有生物亲和力，可以探索与其他治疗靶点相互作用，以协助药物发现。将药物分子和表征的 FDP 进行三维精确（3D-XP）-分子对接，以探索 5-LOX 酶（PDB ID：3V99）的生物亲和力变化。发现一种 FDP 的结合亲和力高于药物本身，表明其可能是一种合适的抗哮喘药物。不能忽视其在其他部位可能具有活性的可能性，通过对物质活性谱的预测（PASS）可以在一定程度上进行评估。除了具有抗哮喘作用外，一些 FDP 还被预测具有抗肿瘤、抗过敏和补体因子-D 抑制剂的作用。
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