Abu Khalaf Reema, Lafi Ala'a, Hajjo Rima, Al-Sha'er Mahmoud A
Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, 11733, Jordan.
Department of Pharmacy, Faculty of Pharmacy, Zarqa University, Zarqa, 13132, Jordan.
Curr Comput Aided Drug Des. 2024 Feb 27. doi: 10.2174/0115734099292078240218095540.
Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL.
This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship.
The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis.
Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness.
It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.
高脂血症的特征是血清胆固醇、甘油三酯异常升高或两者皆有。低密度脂蛋白（LDL）水平升高与心血管疾病之间的关系已得到充分证实。胆固醇酯转移蛋白（CETP）是一种在LDL、极低密度脂蛋白（VLDL）和高密度脂蛋白（HDL）之间转运胆固醇酯和甘油三酯的酶。抑制CETP可通过升高HDL和降低LDL来减少心血管疾病。
本研究合成了10种间氯苯磺酰胺6a - 6j，并探索它们的构效关系。
使用1H - NMR、13C - NMR、红外光谱（IR）和高分辨质谱（HR - MS）对合成的分子进行表征。此外，化学信息学分析包括药效团映射、LibDock研究以及使用二维（2D）分子描述符和主成分分析进行化学信息学表征。
基于体外功能性CETP测定，化合物6e、6i和6j对CETP表现出最强的抑制活性，抑制率达100%。在10 μM浓度下，化合物6a - 6d和6f - 6h的抑制活性范围为47.5%至96.5%。药效团映射结果表明存在CETP抑制作用，而对接分数和计算出的结合能预测有利于在CETP活性位点结合。得分最高的对接构象预测出与His232和Cys13关键相互作用对应的关键疏水特征。使用2D分子描述符的化学信息学分析表明，合成的化合物具有多种物理化学性质和类药性。
发现邻位的氯原子或间位和对位的硝基可提高合成类似物的CETP抑制活性。计算研究表明化合物6a - 6j与CETP之间形成了稳定的配体 - 蛋白质复合物。
