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Estudos in silico da interação da enzima InhA de Mycobacterium tuberculosis com pequenas moléculas do tipo fármaco

机译：结核分枝杆菌InhA酶与小分子药物相互作用的计算机模拟研究

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摘要

The inhA gene from Mycobacterium tuberculosis (Mtb), encodes for an enoyl acyl carrier protein reductase, InhA, a key enzyme of the mycobacterial type II fatty acid elongation cycle and has been validated as an effective target for the development of anti-microbial agents. InhA catalyzes the NADH-dependent reduction of trans double bond between positions C2 and C3 of fatty acyl substrates. It is the target of isoniazid, a first line drug in the tuberculosis treatment. Mutations in InhA structural gene are associated with isoniazid resistance in vivo. Even though mutations within the inhA gene are known to facilitate isoniazid resistance, InhA remains a good candidate for drug design because: (i) the vast majority of the mutations found in isoniazid-resistant clinical isolates are associated with the isoniazid activator (KatG catalase-peroxidase); (ii) only one enoyl-ACP reductase is found in Mtb, unlike some of the other enzymes of bacterial FAS-II systems; (iii) the longer substrate chain length specificity of InhA distinguishes it from the enoyl-ACP reductases from other sources. Our goal with this work was to analyze in detail the structural and physicochemical available information about Mtb InhA using bioinformatics tools. As a result, we developed a pharmacophoric model based on the InhA substrate binding cavity that allowed the application of a virtual screening methodology focused in selecting ligands that satisfied these features, allowing so, a best complementarity with the target protein. Besides we tested the hability of four docking algorithms to find similar conformation to a molecule, providing clues that this would be the conformation closest that adopted in vivo. Finally, molecular dynamics simulations were employed to achieve a better comprehension of the interaction between InhA and a known inhibitor.
机译：来自结核分枝杆菌（Mtb）的inhA基因编码烯酰基酰基载体蛋白还原酶InhA，它是分枝杆菌II型脂肪酸延长周期的关键酶，并且已被确认为开发抗微生物剂的有效靶标。 InhA催化脂肪酰基底物C2和C3位之间反式双键的NADH依赖性还原。它是异烟肼的靶标，这是结核病治疗的一线药物。 InhA结构基因的突变与体内异烟肼抗性有关。即使已知inhA基因内的突变会促进异烟肼耐药性，但InhA仍然是药物设计的良好候选者，因为：（i）异烟肼耐药临床分离株中发现的绝大多数突变都与异烟肼激活剂（KatG过氧化氢酶-过氧化物酶）; （ii）与细菌FAS-II系统的其他一些酶不同，在Mtb中仅发现一种烯酰ACP还原酶； （iii）InhA较长的底物链长度特异性将其与其他来源的烯酰ACP还原酶区分开来。我们这项工作的目标是使用生物信息学工具详细分析有关Mtb InhA的结构和物理化学可用信息。结果，我们开发了基于InhA底物结合腔的药效学模型，该模型允许应用虚拟筛选方法，重点是选择满足这些特征的配体，从而实现与目标蛋白质的最佳互补性。此外，我们还测试了四种对接算法的能力，以找到与分子相似的构象，并提供线索表明这将是体内采用的最接近的构象。最后，采用分子动力学模拟来更好地理解InhA与已知抑制剂之间的相互作用。

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    Pauli Ivani;

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  • 年度 2011
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