Dasgupta Sanjukta
Department of Biotechnology, Center for Multidisciplinary Research & Innovations, Brainware University, Kolkata, West Bengal, India.
OMICS. 2025 Mar;29(3):87-95. doi: 10.1089/omi.2024.0213. Epub 2025 Feb 3.
Innovation in drug discovery for human diseases stands to benefit from systems science and next-generation phenomics approaches. An example is idiopathic pulmonary fibrosis (IPF) that is a chronic pulmonary disorder leading to respiratory failure and for which preventive and therapeutic medicines are sorely needed. Matrix metalloproteinases (MMPs), particularly MMP1 and MMP7, have been associated with IPF pathogenesis and are thus relevant to IPF drug discovery. This study evaluates the comparative therapeutic potentials of doxycycline, pirfenidone, and nintedanib in relation to MMP1 and MMP7 using molecular docking, molecular dynamics simulations, and a next-generation phenomics approach. Adsorption, distribution, metabolism, excretion, and toxicity analysis revealed that doxycycline and nintedanib adhered to Lipinski's rule of five, while pirfenidone exhibited no violations. The toxicity analysis revealed favorable safety profiles, with lethal dose 50 values of doxycycline, pirfenidone, and nintedanib being 2240kg, 580, and 500 mg/kg, respectively. Homology modeling validated the accuracy of the structures of the target proteins, that is, MMP1 and MMP7. The Protein Contacts Atlas tool, a next-generation phenomics platform that broadens the scope of phenomics research, was employed to visualize protein contacts at atomic levels, revealing interaction surfaces in MMP1 and MMP7. Docking studies revealed that nintedanib exhibited superior binding affinities with the candidate proteins (-6.9 kcal/mol for MMP1 and -7.9 kcal/mol for MMP7) compared with doxycycline and pirfenidone. Molecular dynamics simulations further demonstrated the stability of protein-ligand complexes. These findings highlight the notable potential of nintedanib in relation to future IPF therapeutics innovation. By integrating and a next-generation phenomics approach, this study opens up new avenues for drug discovery and development for IPF and possibly, for precision/personalized medicines that consider the molecular signatures of therapeutic candidates for each patient.
人类疾病药物研发领域的创新有望受益于系统科学和新一代表型组学方法。特发性肺纤维化（IPF）就是一个例子，它是一种导致呼吸衰竭的慢性肺部疾病，急需预防和治疗药物。基质金属蛋白酶（MMPs），尤其是MMP1和MMP7，与IPF发病机制相关，因此与IPF药物研发有关。本研究使用分子对接、分子动力学模拟和新一代表型组学方法，评估了多西环素、吡非尼酮和尼达尼布相对于MMP1和MMP7的比较治疗潜力。吸收、分布、代谢、排泄和毒性分析表明，多西环素和尼达尼布符合Lipinski的五规则，而吡非尼酮未出现违规情况。毒性分析显示出良好的安全性，多西环素、吡非尼酮和尼达尼布的半数致死剂量值分别为2240mg/kg、580mg/kg和500mg/kg。同源建模验证了目标蛋白即MMP1和MMP7结构的准确性。蛋白质接触图谱工具是一个拓宽表型组学研究范围的新一代表型组学平台，用于在原子水平可视化蛋白质接触，揭示MMP1和MMP7中的相互作用表面。对接研究表明，与多西环素和吡非尼酮相比，尼达尼布与候选蛋白表现出更高的结合亲和力（MMP1为-6.9 kcal/mol，MMP7为-7.9 kcal/mol）。分子动力学模拟进一步证明了蛋白质-配体复合物的稳定性。这些发现突出了尼达尼布在未来IPF治疗创新方面的显著潜力。通过整合[此处原文缺失相关内容]和新一代表型组学方法，本研究为IPF以及可能为考虑每个患者治疗候选分子特征的精准/个性化药物的药物发现和开发开辟了新途径。
