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<p>Mesalazine (<b>MES</b>) is a first-line therapy for inflammatory bowel disease (IBD); however, its clinical use is limited by variable patient response, intolerance, and reduced efficacy in severe cases. To address these challenges, we have designed and evaluated seventeen <b>MES</b> derivatives (<b>M1</b>–<b>M17</b>) using a comprehensive in silico strategy. Density functional theory with the B3LYP/6-311++G(d,p) basis set was employed to optimize geometries and explore electronic structure, stability, and reactivity. Structural characterization was further supported by FTIR and UV–visible spectral analysis. Molecular docking against five key IBD-associated targets (TNF, NOD2, ATG16L1, IL23R, and IL6) reveled that <b>M1</b>, <b>M5</b>–<b>M8</b>, <b>M10</b>, <b>M11</b>, <b>M14</b>, <b>M16</b>, and <b>M17</b> showed stronger binding affinities than <b>MES</b>, where the <b>M6</b> and <b>M8</b> showed the strongest binding affinity. <b>MES</b> was more toxic towards the human body, although some of its derivatives were less toxic compared to <b>MES</b>, while <b>M8</b> demonstrated an overall improved ADMET profile as an IBD medication. Molecular dynamics simulations of both <b>M8</b>–NOD2 and <b>MES</b>–NOD2 complexes revealed stable behavior in each system; however, <b>M8</b> reduced structural fluctuations, flexibility, and solvent exposure, whereas <b>MES</b> promoted a more compact and conformationally restricted state, indicating distinct stabilization mechanisms, with <b>M8</b> demonstrating superior dynamic control. Collectively, these findings identify <b>M8</b> as a promising drug candidate for IBD, warranting further experimental validation through in vitro and in vivo studies.</p>

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Computational design and in silico evaluation of mesalazine derivatives for enhanced treatment of inflammatory bowel disease

  • 期刊论文

  • 发表日期：

    2026年5月11日

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  • Md. Sohel Rana,
  • Md Fazlay Rabbi,
  • Enamul Haq Rana,
  • Md. Tanvir Islam,
  • Md. Sanoar Hossain,
  • Shamiha Binte Matin,
  • Muhtadi Farjana,
  • Intisar Hussain Wasick,
  • Neeraj Kumar,
  • Md. Kudrat-E-Zahan

摘要

Mesalazine (MES) is a first-line therapy for inflammatory bowel disease (IBD); however, its clinical use is limited by variable patient response, intolerance, and reduced efficacy in severe cases. To address these challenges, we have designed and evaluated seventeen MES derivatives (M1–M17) using a comprehensive in silico strategy. Density functional theory with the B3LYP/6-311++G(d,p) basis set was employed to optimize geometries and explore electronic structure, stability, and reactivity. Structural characterization was further supported by FTIR and UV–visible spectral analysis. Molecular docking against five key IBD-associated targets (TNF, NOD2, ATG16L1, IL23R, and IL6) reveled that M1, M5–M8, M10, M11, M14, M16, and M17 showed stronger binding affinities than MES, where the M6 and M8 showed the strongest binding affinity. MES was more toxic towards the human body, although some of its derivatives were less toxic compared to MES, while M8 demonstrated an overall improved ADMET profile as an IBD medication. Molecular dynamics simulations of both M8–NOD2 and MES–NOD2 complexes revealed stable behavior in each system; however, M8 reduced structural fluctuations, flexibility, and solvent exposure, whereas MES promoted a more compact and conformationally restricted state, indicating distinct stabilization mechanisms, with M8 demonstrating superior dynamic control. Collectively, these findings identify M8 as a promising drug candidate for IBD, warranting further experimental validation through in vitro and in vivo studies.