Laboratory of Biotechnology and Natural Resources Valorization, Faculty of Sciences, Ibn Zohr University, 80060, Agadir, Morocco.
Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, 6205, Bangladesh.
Med Chem. 2024;20(7):741-751. doi: 10.2174/0115734064295521240227052730.
Inflammatory Bowel Disease (IBD) encompasses a group of chronic disorders distinguished by inflammation of the gastrointestinal tract. Among these, Crohn's Disease (CD) stands out as a complex and impactful condition due to challenges for both diagnosis and management, making it a cynosure of research.
In CD, there is the predominance of proinflammatory bacteria, including the Adherentinvasive Escherichia coli (AIEC) with virulence-associated metabolic enzyme Propanediol Dehydratase (pduC), which has been identified as a therapeutic target for the management of CD. Herein, molecular modeling techniques, including molecular docking, Molecular Mechanics with Generalized Born and Surface Area (MMGBSA), drug-likeness, and pharmacokinetics profiling, were utilized to probe the potentials of eighty antibacterial compounds to serve as inhibitors of pduC.
The results of this study led to the identification of five compounds with promising potentials; the results of the molecular docking simulation revealed the compounds as possessing better binding affinities for the target compared to the standard drug (sulfasalazine), while Lipinski's rule of five-based assessment of their drug-likeness properties revealed them as potential oral drugs. MMGBSA free energy calculation and Molecular Dynamics (MD) simulation of the complexes formed a sequel to molecular docking, revealing the compounds as stable binders in the active site of the protein.
Ultimately, the results of this study have revealed five compounds to possess the potential to serve as inhibitors of pduC of AIEC. However, experimental studies are still needed to validate the findings of this study.
炎症性肠病（IBD）是一组以胃肠道炎症为特征的慢性疾病。其中，克罗恩病（CD）是一种复杂且影响深远的疾病，因为其诊断和管理都存在挑战，因此成为研究的焦点。
在 CD 中，存在以粘附侵袭性大肠杆菌（AIEC）为主的促炎细菌，该细菌具有与毒力相关的代谢酶丙二醇脱水酶（pduC），该酶已被确定为 CD 管理的治疗靶点。在此，利用分子建模技术，包括分子对接、广义 Born 和表面面积的分子力学（MMGBSA）、药物相似性和药代动力学分析，探究了 80 种抗菌化合物作为 pduC 抑制剂的潜力。
本研究的结果确定了 5 种具有潜力的化合物；分子对接模拟的结果表明，与标准药物（柳氮磺胺吡啶）相比，这些化合物对靶标具有更好的结合亲和力，而基于 Lipinski 五规则的药物相似性评估表明它们具有成为潜在口服药物的潜力。复合物的 MMGBSA 自由能计算和分子动力学（MD）模拟是分子对接的后续，表明这些化合物是蛋白质活性部位的稳定配体。
最终，本研究的结果表明，有 5 种化合物具有作为 AIEC pduC 抑制剂的潜力。然而，仍需要进行实验研究来验证本研究的结果。
