Department of Medical Microbiology, Faculty of Medicine, University of Tabuk, Tabuk; Postal Code: 71491; P.O. Box: 741 Kingdom of Saudi Arabia.
Dr. Panjwani Center for Molecular Medicine and Drug Research (PCMD), International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Curr Comput Aided Drug Des. 2022;18(2):110-119. doi: 10.2174/1573409917666211118094840.
Smokeless tobacco (SLT) is traditionally used in Middle East countries. The several toxic constituents with potential carcinogenicity make it a serious human health risk. Literature regarding their effects on cardiac and cancer disease is lacking in Saudi Arabia.
This study was conducted to investigate the adverse effect of 11 different samples of widely used SLT varieties from the Tabuk region - Saudi Arabia, on Nitric Oxide (NO) level and their potential risk on cardiovascular health, etiology and/or progression of cancers.
Samples were collected from Tabuk, KSA and analyzed by the GC-MS technique. Nitric oxide inhibition was performed using J774.2 macrophages by the Griess method. The retrieved crystallized structure of human inducible nitric oxide synthase (iNOS) from Brookhaven Protein Data Bank Repository PDB I.D: 3E7G with 2.20Å resolution was further prepared by structure using the MOE.2019 tool. The compounds abstracted from 11 different Shammah varieties were sketched by the MOE-Builder tool. Minimization for both receptor and compounds was performed via AMBER99 and MMFF99X force field implemented in MOE.
Nine samples (4 - 11) showed a potent suppressive effect on NO production with IC50 values ranging between (16.9-20.4 μg/mL), respectively. The samples (1 & 2) exhibited a moderate level of inhibition with IC50 ranging between 33.2 and 57.4 μg/mL, respectively. Interestingly, sample 4 consisting of compounds (13-15, 19-26, 28) that mostly belongs to the group fatty acid ester and phthalic acid ester showed the most potent suppressive effect. Molecular docking results revealed that the current local SLT constituents presented noticeable potency in different extract samples.
Variable suppressive effects on NO were detected in the current SLT samples, where sample 4 was the most potent among all. The extract of the latter exhibited molecular interaction with the first shell amino acid residues of Inducible nitric oxide synthase (iNOS), which may anchor the plasticity and selectivity of the compounds present in it. The samples (4 -11) showed a potent inhibitory effect on the NO, where compound 26 (Phthalic acid ester) is common, and its adequate concentration may account for augmented biological activity. These results may effectively highlight their adverse effects on cardiovascular health and etiology and/or progression of cancer and may help in strengthening the social and governmental efforts in minimizing the use of these substances.
无烟烟草（SLT）在中东国家传统上被使用。它含有多种有毒成分，具有潜在的致癌性，对人类健康构成严重威胁。然而，沙特阿拉伯缺乏关于其对心脏和癌症疾病影响的相关文献。
本研究旨在调查来自沙特阿拉伯塔布克地区广泛使用的 11 种不同 SLT 品种对一氧化氮（NO）水平的不良影响，以及它们对心血管健康、癌症病因和/或进展的潜在风险。
从沙特阿拉伯的塔布克采集样本，并使用 GC-MS 技术进行分析。通过 Griess 法在 J774.2 巨噬细胞中进行一氧化氮抑制实验。从 Brookhaven Protein Data Bank Repository PDB I.D：3E7G 中检索出人诱导型一氧化氮合酶（iNOS）的结晶结构，分辨率为 2.20Å，然后使用 MOE.2019 工具进行结构准备。通过 MOE-Builder 工具对 11 种不同 Shamah 品种中提取的化合物进行草图绘制。通过 AMBER99 和 MMFF99X 力场在 MOE 中对受体和化合物进行最小化处理。
其中 9 个样本（4-11）显示出对 NO 产生的强烈抑制作用，IC50 值在 16.9-20.4μg/mL 之间。样本 1 和 2 显示出中等水平的抑制作用，IC50 值分别在 33.2 和 57.4μg/mL 之间。有趣的是，由化合物（13-15、19-26、28）组成的样本 4 主要属于脂肪酸酯和邻苯二甲酸酯组，表现出最强的抑制作用。分子对接结果表明，目前当地的 SLT 成分在不同的提取物样品中表现出显著的效力。
当前 SLT 样品对 NO 表现出不同程度的抑制作用，其中样本 4 的抑制作用最强。后者的提取物与诱导型一氧化氮合酶（iNOS）的第一壳层氨基酸残基发生分子相互作用，这可能固定了其中存在的化合物的可塑性和选择性。样品 4-11 对 NO 表现出强烈的抑制作用，其中常见的化合物 26（邻苯二甲酸酯），其适当的浓度可能导致其生物活性增强。这些结果可能有效地强调它们对心血管健康以及癌症的病因和/或进展的不良影响，并有助于加强社会和政府在减少这些物质使用方面的努力。
