Abdullah Shawana, Iqbal Ambar, Ashok Avinash Karkada, Kaouche Farah Chafika, Aslam Misbah, Hussain Safdar, Rahman Jameel, Hayat Muhammad Munawar, Ashraf Muhammad
Institute of Chemistry, Baghdad-ul-Jadeed Campus, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan.
Department of Biochemistry and Molecular Biology, Institute of Biochemistry, Biotechnology & Bioinformatics, Baghdad-ul-Jadeed Campus, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan.
Heliyon. 2024 Jan 12;10(2):e24470. doi: 10.1016/j.heliyon.2024.e24470. eCollection 2024 Jan 30.
Montelukast, an approved leukotriene receptor 1 (Cys-LT 1) antagonist with anti-inflammatory properties is used for the treatment of asthma and allergic rhinitis. In the present studies, montelukast was subjected to inhibitory assays followed by kinetic and investigations. Montelukast demonstrated inhibitory activity against yeast α-glucosidase (IC 44.31 ± 1.21 μM), jack bean urease (JB urease, IC 8.72 ± 0.23 μM), human placental alkaline phosphatase (hPAP, IC 17.53 ± 0.19 μM), bovine intestinal alkaline phosphatase (bIAP, IC 15.18 ± 0.23 μM) and soybean 15-lipoxygenase (15-LOX, IC 2.41 ± 0.13 μM). Kinetic studies against α-glucosidase and urease enzymes revealed its competitive mode of inhibition. Molecular expression analysis of montelukast in breast cancer cell line MCF-7 down-regulated AP by a factor of 0.27 (5 μM) compared with the 0.26 value for standard inhibitor levamisole (10 μM). Molecular docking estimated a binding affinity ranging -8.82 to -15.65 kcal/mol for the enzymes. Docking against the DNA dodecamer (ID: 1BNA) observed -9.13 kcal/mol via minor groove binding. MD simulations suggested stable binding between montelukast and the target proteins predicting strong inhibitory potential of the ligand. Montelukast features a chloroquinoline, phenyl ring, a cyclopropane group, a carboxylic group and a sulfur atom all of which collectively enhance its inhibitory potential against the said enzymes. These and computational investigations demonstrate that it is possible and suggested that the interactions of montelukast with more than one targets presented herein may be linked with the side effects presented by this drug and necessitate additional work. The results altogether suggest montelukast as an important structural scaffold possessing multitargeted features and warrant further investigations in repurposing beyond its traditional pharmacological use.
孟鲁司特是一种已获批准的具有抗炎特性的白三烯受体1（半胱氨酰白三烯受体1，Cys-LT1）拮抗剂，用于治疗哮喘和过敏性鼻炎。在本研究中，对孟鲁司特进行了抑制试验，随后进行了动力学和[此处原文缺失部分内容]研究。孟鲁司特对酵母α-葡萄糖苷酶（IC50为44.31±1.21μM）、刀豆脲酶（JB脲酶，IC50为8.72±0.23μM）、人胎盘碱性磷酸酶（hPAP，IC50为17.53±0.19μM）、牛小肠碱性磷酸酶（bIAP，IC50为15.18±0.23μM）和大豆15-脂氧合酶（15-LOX，IC50为2.41±0.13μM）均表现出抑制活性。针对α-葡萄糖苷酶和脲酶的动力学研究揭示了其竞争性抑制模式。与标准抑制剂左旋咪唑（10μM）的0.26值相比，孟鲁司特在乳腺癌细胞系MCF-7中的分子表达分析使碱性磷酸酶（AP）下调了0.27倍（5μM）。分子对接估计该酶的结合亲和力范围为-8.82至-15.65千卡/摩尔。通过小沟结合对接DNA十二聚体（ID：1BNA）观察到结合亲和力为-9.13千卡/摩尔。分子动力学模拟表明孟鲁司特与靶蛋白之间的结合稳定，预测该配体具有强大的抑制潜力。孟鲁司特具有一个氯喹啉、一个苯环、一个环丙烷基团、一个羧基和一个硫原子，所有这些共同增强了其对上述酶的抑制潜力。这些[此处原文缺失部分内容]和计算研究表明这是可能的，并表明孟鲁司特与本文所述多个靶点的相互作用可能与其该药物所呈现的副作用有关，需要进一步研究。总体结果表明孟鲁司特是一种具有多靶点特征的重要结构支架，值得在其传统药理学用途之外的重新利用方面进行进一步研究。
