Cheminformatics approaches to predict the bioactivity and to discover the pharmacophoric traits crucial to block NF-κB

IF 3.8 Q2 CHEMISTRY, PHYSICAL Chemical Physics Impact Pub Date : 2024-09-05 DOI:10.1016/j.chphi.2024.100720
Rahul D. Jawarkar , Suraj N. Mali , Rahul G. Ingle , Sami A. Al-Hussain , Aamal A. Al-Mutairi , Prashant Deshmukh , Magdi E.A. Zaki
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Abstract

Many human disorders include NF-kB signaling pathways, making IKK a therapeutic target in cancer treatment. Inflammatory illnesses and cancer are examples. COVID-19 is one of several triggers that stimulate NF-kB signaling. The activation of the NF-kB pathway is necessary for COVID-19 to cease its development. To learn more about the mechanism and structural features essential to IKK inhibition (IC50), molecular modeling studies have been undertaken on experimentally reported 503. QSAR analysis explores certain reported and hidden structural features critical for IKKβ inhibition. The OECD guidelines guided the construction of the QSAR model, which achieved all the endorsed threshold values for all validation parameters (R2tr:0.81, R2LMO:0.80, and R2ext:0.78). The present QSAR study shows that IKK inhibitory activity is linked to the following structural features: lipophilic hydrogen atoms within 2 A units of the molecule's center of mass; ring nitrogen atoms within one bond of planar nitrogen atoms; ring carbon atoms exactly four bonds from the non-ring nitrogen atoms; planar nitrogen atoms exactly four bonds from sp2 hybridized carbon atoms; and so on. Pharmacophore modeling highlighted QSAR-identified structural characteristics. To investigate binding, we docked all 503 molecules. The observation indicates that the QSAR and molecular docking/pharmacophore modeling findings are in agreement. Following this, we conducted 200 ns of molecular dynamics simulation to validate the molecular docking protocol. MMGBSA analysis determined the binding energy of the dock complex. Thus, the current study found unique pharmacophoric properties that may assist in optimizing lead/hit compounds for anti-IKKβ activity.

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用化学信息学方法预测生物活性并发现阻断 NF-κB 的关键药效特征
许多人类疾病都包含 NF-kB 信号通路,这使得 IKK 成为癌症治疗的一个靶点。炎症性疾病和癌症就是例子。COVID-19 是刺激 NF-kB 信号传导的几种诱因之一。激活 NF-kB 通路是 COVID-19 停止发展的必要条件。为了进一步了解 IKK 抑制作用(IC50)的机制和结构特征,对实验报告的 503 进行了分子建模研究。QSAR 分析探索了某些已报道和隐藏的对 IKKβ 抑制作用至关重要的结构特征。在 OECD 准则的指导下构建了 QSAR 模型,该模型的所有验证参数都达到了认可的阈值(R2tr:0.81、R2LMO:0.80 和 R2ext:0.78)。本 QSAR 研究表明,IKK 抑制活性与以下结构特征有关:分子质心 2 A 单位范围内的亲脂性氢原子;平面氮原子一个键范围内的环状氮原子;与非环状氮原子正好相距四个键的环状碳原子;与 sp2 杂化碳原子正好相距四个键的平面氮原子等。药效学建模突出了 QSAR 确定的结构特征。为了研究结合情况,我们对接了所有 503 个分子。观察结果表明,QSAR 和分子对接/药层建模结果是一致的。随后,我们进行了 200 ns 的分子动力学模拟,以验证分子对接方案。MMGBSA 分析确定了对接复合物的结合能。因此,目前的研究发现了一些独特的药效特性,这些特性可能有助于优化具有抗IKKβ活性的先导/命中化合物。
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来源期刊
Chemical Physics Impact
Chemical Physics Impact Materials Science-Materials Science (miscellaneous)
CiteScore
2.60
自引率
0.00%
发文量
65
审稿时长
46 days
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