Scholarlink

<p>Tuberculosis remains a critical global health challenge, necessitating the urgent development of novel therapeutics. In this study, we employed an integrated computational approach to design and evaluate potent inhibitors targeting enoyl-acyl carrier protein reductase (InhA) in <i>Mycobacterium tuberculosis</i>. A robust 2D quantitative structure–activity relationship (QSAR) model was developed, demonstrating high predictive accuracy (R<sup>2</sup> = 0.966, Q<sup>2</sup>LOO = 0.957) and interpretability through descriptors AATSC6i, SCH-5, and maxdssC. Molecular docking studies identified compounds with superior binding affinities, notably Compound 14 (− 118.234&#xa0;kcal/mol), which exhibited key interactions with active-site residues such as ALA191 and ILE215. Density functional theory (DFT) calculations provided insights into electronic properties and reactivity, confirming the stability of lead compounds. Drug-likeness and ADMET profiling revealed favourable pharmacokinetic properties, including high intestinal absorption and minimal toxicity risks. Based on its favourable binding profile and non-toxic ADMET properties, compound 14 was selected as a template for designing two novel derivatives. These analogues demonstrated improved docking scores (− 132.579 and − 125.894&#xa0;kcal/mol), high intestinal absorption (&gt; 88%), and no predicted toxicity, underscoring their potential as effective InhA inhibitors. Molecular dynamics simulations over 250&#xa0;ns further validated the stability and binding modes of top candidates, with MM/GBSA calculations highlighting the significance of van der Waals and hydrophobic interactions. These findings position compound 14 and its derivatives as promising candidates for further preclinical development in tuberculosis therapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

In Silico design and evaluation of novel anti-tubercular agents as Inha inhibitors through a virtual screening approach

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月1日

查看全文
  • Thomas Aondofa Nyijime,
  • Gideon Adamu Shallangwa,
  • Adamu Uzairu,
  • Abdullahi Bello Umar,
  • Muhammad Tukur Ibrahim,
  • Mohnad Abdalla,
  • Abdullah Hamadi,
  • Jameel Barnawi,
  • Hassan A. Madkhali

摘要

Tuberculosis remains a critical global health challenge, necessitating the urgent development of novel therapeutics. In this study, we employed an integrated computational approach to design and evaluate potent inhibitors targeting enoyl-acyl carrier protein reductase (InhA) in Mycobacterium tuberculosis. A robust 2D quantitative structure–activity relationship (QSAR) model was developed, demonstrating high predictive accuracy (R2 = 0.966, Q2LOO = 0.957) and interpretability through descriptors AATSC6i, SCH-5, and maxdssC. Molecular docking studies identified compounds with superior binding affinities, notably Compound 14 (− 118.234 kcal/mol), which exhibited key interactions with active-site residues such as ALA191 and ILE215. Density functional theory (DFT) calculations provided insights into electronic properties and reactivity, confirming the stability of lead compounds. Drug-likeness and ADMET profiling revealed favourable pharmacokinetic properties, including high intestinal absorption and minimal toxicity risks. Based on its favourable binding profile and non-toxic ADMET properties, compound 14 was selected as a template for designing two novel derivatives. These analogues demonstrated improved docking scores (− 132.579 and − 125.894 kcal/mol), high intestinal absorption (> 88%), and no predicted toxicity, underscoring their potential as effective InhA inhibitors. Molecular dynamics simulations over 250 ns further validated the stability and binding modes of top candidates, with MM/GBSA calculations highlighting the significance of van der Waals and hydrophobic interactions. These findings position compound 14 and its derivatives as promising candidates for further preclinical development in tuberculosis therapy.