MOLECULAR DOCKING AND MOLECULAR DYNAMICS STUDIES OF THE INTERACTION BETWEEN COUMARIN-NEUROTRANSMITTER DERIVATIVES AND CARBONIC ANHYDRASE IX

D. Dimić, D. Milenkovic, Edina H. Avdović, G. Kaluđerović, Jasmina M. Dimitrić Marković
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Abstract

Novel biologically active compounds can be obtained by the structural modification of coumarins. In this contribution, five new derivatives of 4-hydroxycoumarin with tyramine, octopamine, norepinephrine, 3-methoxytyramine, and dopamine were obtained. Their structures were optimized based on the previously obtained crystal structure of the 4-hydroxycoumarin-dopamine derivative. The special emphasis was put on the effect of various substituents on the structure of obtained compounds and intramolecular interactions governing the stability. To investigate their possible antitumor activity, molecular docking and molecular dynamics simulations were performed with Carbonic anhydrase, a prognostic factor in several cancers, and compared to the native ligand, 5-acetamido-1,3,4-thiadiazole- 2-sulfonamide. The results have shown that all of the coumarin-neurotransmitter derivatives bind to the active pocket of protein with the binding energies higher than for the native ligand. The main contributions to the binding energies were discussed. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Radius of gyration (Rg), as results of MD simulations, were used to predict the activity of compounds towards chosen protein. The highest MD binding energies were obtained for the derivatives with dopamine and 3-methoxytyramine, with the van der Waals interaction and hydrogen bonds being the most important contributors.
香豆素-神经递质衍生物与碳酸酐酶相互作用的分子对接及分子动力学研究
香豆素的结构修饰可获得新的生物活性化合物。在这篇文章中,得到了5个新的4-羟基香豆素与酪胺、章鱼胺、去甲肾上腺素、3-甲氧基酪胺和多巴胺的衍生物。在先前获得的4-羟基香豆素-多巴胺衍生物晶体结构的基础上,对其结构进行了优化。特别强调了各种取代基对所得化合物结构的影响以及控制稳定性的分子内相互作用。为了研究它们可能的抗肿瘤活性,我们与几种癌症的预后因子碳酸酐酶进行了分子对接和分子动力学模拟,并与天然配体5-乙酰氨基-1,3,4-噻二唑- 2-磺酰胺进行了比较。结果表明,所有香豆素-神经递质衍生物与活性蛋白袋结合的结合能均高于天然配体。讨论了对结合能的主要贡献。均方根偏差(RMSD)、均方根波动(RMSF)和旋转半径(Rg)作为MD模拟的结果,被用来预测化合物对所选蛋白质的活性。含有多巴胺和3-甲氧基酪胺的衍生物的MD结合能最高,其中范德华相互作用和氢键是最重要的贡献者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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