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通过集成的in-silico方法识别结核病的DprE1抑制剂

Swagatika Dash¹, Ekta Rathi¹, Avinash Kumar²

¹Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India, 576104.

Scientific reports

|May 17, 2024

概括

这项研究确定了一种新型化合物,Hit 2,作为Decaprenylphosphoryl-β-D-ribose-2'-epimerase (DprE1) 的有前途的抑制剂,这是结核病药物发现的关键目标. 计算方法证实了它的稳定性和潜力,作为新的抗结核药物的头.

科学领域:

药用化学医学化学
计算生物学计算生物学
药物发现药物发现药物发现

背景情况:

德卡普林酸-β-D-利博-2-表皮酶 (DprE1) 是菌根菌细胞壁生物合成中的关键酶,也是抗结核病 (TB) 药物开发的有希望的目标.
现有的抗结核病疗法因耐药性而面临挑战,需要发现新型治疗剂.

研究的目的:

使用in-silico方法识别DprE1的潜在抑制剂.
开发和验证DprE1抑制剂的药和3D-QSAR模型.
选新的DprE1抑制剂的数据库,并评估它们的药物相似性和疗效.

主要方法:

使用已知的阿赞尔DprE1抑制剂构建药和3D-QSAR模型.
通过使用开发的药模型对ChEMBL数据库进行虚拟选.
分子对接,结合能量的计算 (Prime/MM-GBSA) 和选化合物的药理动力学预测.
分子动力学模拟 (MDS) 用于评估顶部命中酶复合物的稳定性.

主要成果:

一个药模型 (ADRRR_1) 和一个3D-QSAR模型 (R 2 =0.9608,Q 2 =0.7313) 已成功开发.
虚拟查发现了几种潜在的DprE1抑制剂,其中2 (ChEMBL_SDF:357100) 显示出显著的结合亲和力 (< -9.0 kcal/mol).
超过200 ns的分子动力学模拟证实了DprE1的命中2的结构稳定性,支持其作为化合物的潜力.

结论:

标识为 (N-(3-((2-((1r,4r)-4-(dimethylamino) 环) 氨基) -9-异-9H-纯素-6-yl) 氨基) ) 烯胺的Hit 2),是新型DprE1抑制抗结核药物发现的有希望的化合物.
集成的in-silico方法,结合药模拟,QSAR,对接和分子动力学,有效地确定了一个具有有利安全概况的潜在候选药物.
进一步的实验验证是有必要的,以确认击中2作为抗结核病治疗剂的有效性和安全性.

关键词:

结核病菌菌菌的结核病菌的结核病菌.3D-QSAR 是一个3D-QSAR.DprE1E1 在线阅读分子动力学分子动力学药科类动物 (Pharmacophore) 是一种药科类动物.

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