Saravanakumar Natarajan, Aruna Poorani Arunagiri Sivanesan, Latha Ganesapandian, Dhanabalan Anantha Krishnan, Srikanth Srimari, Ulaganathan Venkatasubramanian, Suresh Palaniswamy
Supramolecular and Catalysis Lab, Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu, India.
Department of Chemistry, Sethu Institute of Technology, Virudhunagar, Tamil Nadu, India.
J Comput Aided Mol Des. 2025 Sep 3;39(1):73. doi: 10.1007/s10822-025-00647-8.
TGF-β receptor I kinase plays a significant role in cancer biology and is a well-established target for cancer drug development, as evidenced by active molecules like Galunisertib (LY2157229). Computational studies were conducted to analyse the catalytic site of TGF-β receptor I kinase, identifying key amino acid residues essential for binding. Based on these findings, Alicyclic fused pyrazole derivatives were designed. The target molecules were synthesized through a multi-step process, with an important intermediate obtained via Suzuki coupling, followed by various ligand and catalyst optimizations. A total of thirteen molecules were synthesized by optimizing temperature, solvent, and base. After characterization, the synthesized, Alicyclic fused pyrazole derivatives were screened for TGF-β receptor I kinase inhibition and in vitro cytotoxic activity. To further elucidate their binding mechanism, molecular docking and molecular dynamics studies were performed. The most active compound 16c, was subjected to in silico ADME screening, which revealed a favorable pharmacokinetic profile. Molecular Dynamics simulation study indicated that specific aminoacid residue interaction with TGF-β receptor I kinase. Additionally, DFT calculations were conducted on the active molecules to gain deeper insights into their electronic properties, supporting their potential as effective anticancer agents.
转化生长因子-β受体I激酶在癌症生物学中起着重要作用，并且是癌症药物开发中一个成熟的靶点，像Galunisertib（LY2157229）这样的活性分子就证明了这一点。进行了计算研究以分析转化生长因子-β受体I激酶的催化位点，确定结合所必需的关键氨基酸残基。基于这些发现，设计了脂环族稠合吡唑衍生物。目标分子通过多步过程合成，通过铃木耦合获得重要中间体，随后进行各种配体和催化剂优化。通过优化温度、溶剂和碱总共合成了13个分子。表征后，对合成的脂环族稠合吡唑衍生物进行转化生长因子-β受体I激酶抑制和体外细胞毒性活性筛选。为了进一步阐明它们的结合机制，进行了分子对接和分子动力学研究。最具活性的化合物16c进行了计算机辅助的药物代谢动力学（ADME）筛选，结果显示其具有良好的药代动力学特征。分子动力学模拟研究表明特定氨基酸残基与转化生长因子-β受体I激酶相互作用。此外，对活性分子进行了密度泛函理论（DFT）计算，以更深入了解其电子性质，支持它们作为有效抗癌剂的潜力。
