Padhy Ipsa, Banerjee Biswajit, Sharma Tripti, Achary P Ganga Raju, Singh Nagendra, Chandra Anshuman
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Siksha 'O'Anusandhan (Deemed to Be University), Bhubaneswar, 751003, Odisha, India.
Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Siksha 'O'Anusandhan (Deemed to Be University), Bhubaneswar, 751003, Odisha, India; School of Pharmaceutical Sciences and Research, Chhatrapati Shivaji Maharaj University, Panvel, Navi Mumbai, Maharashtra, India.
Biochem Biophys Res Commun. 2025 Jan;745:151200. doi: 10.1016/j.bbrc.2024.151200. Epub 2024 Dec 18.
A series of ten topiramate-phenolic acid conjugates (T1-T10) were synthesized, and evaluated for their pancreatic lipase inhibitory and antioxidant potentials. The design of the compounds reflected the structural attributes extracted from robust QSAR models developed for predicting the pancreatic lipase inhibition potency. Conjugate T4 competitively inhibited pancreatic lipase with IC value of 8.96 μM, comparable to the standard drug, orlistat (IC = 11.68 μM). Molecular docking of T4 into the active site of human PL (PDB ID: 1LPB) revealed strong binding score of -11.54 kcal/mol. Molecular dynamics simulation of T4 complexed with pancreatic lipase, confirmed the role of phenolic acid core in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD = 3.77 Å). Additionally, T4 with its LUMO (-0.20254) and HOMO (0.30502) values, abstracted from DFT studies, depicts considerable promise in the pursuit of selecting an effective enzyme inhibitor binding to the enzyme's active site and disrupting its catalytic function. The conjugation of topiramate with phenolic acids has imparted potential antioxidant properties to the synthesized conjugates especially T3, T4 and T5. Conclusively, with good safety profile as predicted from in silico ADMET studies, potent pancreatic lipase inhibition and free radical quenching, T4 stands taller as promising anti-obesity drug candidate.
合成了一系列十种托吡酯 - 酚酸共轭物（T1 - T10），并评估了它们对胰脂肪酶的抑制潜力和抗氧化能力。这些化合物的设计反映了从用于预测胰脂肪酶抑制效力的稳健定量构效关系（QSAR）模型中提取的结构特征。共轭物T4对胰脂肪酶具有竞争性抑制作用，IC值为8.96 μM，与标准药物奥利司他（IC = 11.68 μM）相当。T4与人胰脂肪酶（PDB ID：1LPB）活性位点的分子对接显示出 -11.54 kcal/mol的强结合分数。T4与胰脂肪酶复合的分子动力学模拟证实了酚酸核心通过疏水相互作用稳定配体的作用（观察到的最大均方根偏差 = 3.77 Å）。此外，从密度泛函理论（DFT）研究中得出的T4的最低未占分子轨道（LUMO，-0.20254）和最高已占分子轨道（HOMO，0.30502）值表明，在选择与酶活性位点结合并破坏其催化功能的有效酶抑制剂方面具有很大潜力。托吡酯与酚酸的共轭赋予了合成的共轭物，特别是T3、T4和T5潜在的抗氧化特性。总之，根据计算机辅助药物代谢动力学（ADMET）研究预测，T4具有良好的安全性、强大的胰脂肪酶抑制作用和自由基淬灭能力，作为有前景的抗肥胖药物候选物脱颖而出。
