计算三维结构预测,然后进行分子对接,揭示针对ADA的新药物靶点

Noel Shamaun, M. I. Fareed, Keziah Shaheen, Muhammad Ameer Moaavia, Aksa Khalid, Sonana Nadeem, Sehrish Naz, M. Fareed, MA Moaavia
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摘要

腺苷脱氨酶(ADA)是一种将脱氧腺苷和腺苷分别转化为脱氧肌苷和肌苷的功能酶。ADA缺乏导致有毒嘌呤降解副产物在体内积累,对淋巴细胞产生特别负面的影响,导致腺苷脱氨酶缺乏严重的联合免疫缺陷。采用不同的计算机技术,包括线程、从头算和同源建模的三维结构预测,用于ADA结构的预测。在三维结构预测分析之后,对所有预测结构的可靠性进行了广泛的计算评估。在预测的三维模型中,预测的ADA结构的整体质量因子为62.45%。建立了Ramachandran图,94.80%的残基位于蛋白质结构图的允许和有利区域。进行分子对接分析,以确定针对ADA的潜在治疗药物靶点。通过高通量筛选得到的分子可能具有调节ADA活性的能力。通过分子对接分析计算出最小结合能,能量值为-8.7 Kcal/mol。结合残基(Lys-367、Glu-424、Asp-422、ph -381、Ile-377、Ser-430和Glu-374)在所有对接物的相互作用分析中都是保守的。在蛋白质三维结构中找到有效的结合域对于了解其结构组成和确定其功能至关重要。
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Computational 3D structure prediction followed by molecular docking to reveal the novel drug targets against ADA
Adenosine deaminase (ADA) is a functional enzyme that transforms deoxyadenosine and adenosine into deoxyinosine and inosine respectively. ADA deficiency causes toxic purine degradation byproducts to build up in the body, which has a particularly negative impact on lymphocytes and results in adenosine deaminase-deficient severe combined immunodeficiency. Different in silico techniques including threading, ab initio and homology modeling for 3D structure prediction were applied for the prediction of ADA structures. Following the three-dimensional structure prediction analyses, an extensive computational assessment of all predicted structures for reliability was performed. The overall quality factor of the predicted ADA structures was observed 62.45% in the predicted 3D models. A Ramachandran plot was created, and 94.80% of the residues were found in the allowed and favored regions of the protein structure plot. The molecular docking analyses were performed in order to identify the potential therapeutic medication targets against ADA. The virtually examined molecules through a virtually high throughput screening may have the ability the regulation the ADA activity. The least binding energy was calculated through the molecular docking analyses and the energy values were observed -8.7 Kcal/mol. The binding residues (Lys-367, Glu-424, Asp-422, Phe-381, Ile-377, Ser-430 and Glu-374) were conserved in all the interactional analyses of the docked complexes. Finding the effective binding domain in a protein three-dimensional structure is crucial for understanding of its structural makeup and determining its functions.
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