Postgraduate Program of Natural and Synthetic Bioactive Products (PgPNSB), Health Sciences Center, Federal University of Paraiba, Joao Pessoa-PB, Brazil.
Comb Chem High Throughput Screen. 2020;23(6):504-516. doi: 10.2174/1386207323666200226094940.
Tuberculosis is a disease with high incidence and high mortality rate, especially in Brazil. Although there are several medications available for treatment, in cases of resistance, there is a need to use more than one medication.
Therefore, cases of toxicity increase and reports of resistance have been worrying the population. In addition, some medications have a short period of effectiveness. To achieve the goal, ligand-based and structure-based approaches were used.
Thus, in an attempt to discover potent inhibitors against Mycobacterium tuberculosis enzymes, we sought to identify natural products with high therapeutic potential for the treatment of Tuberculosis through QSAR, Molecular Modeling and ADMET studies.
The results showed that the models generated from two sets of molecules with known activity against M. tuberculosis enzymes InhA and PS were able to select 11 and 8 compounds, respectively, between Lignans and Neolignans with 50 to 60% activity probability. In addition, molecular docking contributed to confirm the mechanism of action of compounds and increase the accuracy of methodologies. All molecules showed higher binding energy values for the drug Isoniazid. We conclude that compounds 33, 34, 110, 114 and 133 are promising for InhA target and compounds 07, 08, 19, 21, 42, 48, 75 and 141 for target PS. In addition, most molecules did not show any toxicity according to the evaluated parameters.
Therefore, Lignans and Neolignans may be an alternative for the treatment of Tuberculosis.
结核病是一种发病率和死亡率都很高的疾病，尤其是在巴西。尽管有几种药物可用于治疗，但在出现耐药性的情况下，需要使用多种药物。
因此，毒性病例增加和耐药性报告令人担忧。此外，一些药物的有效期较短。为了实现这一目标，采用了基于配体和基于结构的方法。
因此，为了寻找针对结核分枝杆菌酶的有效抑制剂，我们试图通过 QSAR、分子建模和 ADMET 研究，从天然产物中发现具有治疗结核病高治疗潜力的天然产物。
结果表明，从具有已知抗结核分枝杆菌酶 InhA 和 PS 活性的两组分子生成的模型，分别能够选择分别具有 50%至 60%活性概率的木脂素和新木脂素的 11 种和 8 种化合物。此外，分子对接有助于确认化合物的作用机制并提高方法的准确性。所有分子对药物异烟肼的结合能值都更高。我们得出结论，化合物 33、34、110、114 和 133 对 InhA 靶标有希望，化合物 07、08、19、21、42、48、75 和 141 对 PS 靶标有希望。此外，根据评估的参数，大多数分子没有显示出任何毒性。
因此，木脂素和新木脂素可能是治疗结核病的一种选择。
