Department of Pharmacy, Banasthali University, Banasthali, Rajasthan, 304022, India.
Medical Department, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India.
Curr Drug Discov Technol. 2024;21(2):e010923220643. doi: 10.2174/1570163820666230901144003.
Metabolic syndrome is one of the major non-communicable global health hazards of the modern world owing to its amplifying prevalence. Acetyl coenzyme-A carboxylase 2 (ACC 2) is one of the most crucial enzymes involved in the manifestation of this disease because of its regulatory role in fatty acid metabolism.
To find novel potent ACC 2 inhibitors as therapeutic potential leads for combating metabolic syndrome.
In the present study, a two-dimensional quantitative structure-activity relationship (2D QSAR) approach was executed on biologically relevant thiazolyl phenyl ether derivatives as ACC 2 inhibitors for structural optimization. The physiochemical descriptors were calculated and thus a correlation was derived between the observed and predicted activity by the regression equation. The significant descriptors i.e. log P (Whole Molecule) and Number of H-bond Donors (Substituent 1) obtained under study were considered for the design of new compounds and their predicted biological activity was calculated from the regression equation of the developed model. The compounds were further validated by docking studies with the prepared ACC 2 receptor.
The most promising predicted leads with the absence of an H-bond donor group at the substituted phenyl ether moiety yet increased overall lipophilicity exhibited excellent amino acid binding affinity with the receptor and showed predicted inhibitory activity of 0.0025 μM and 0.0027 μM. The newly designed compounds were checked for their novelty. Lipinski's rule of five was applied to check their druggability and no violation of this rule was observed.
The compounds designed in the present study have tremendous potential to yield orally active ACC 2 inhibitors to treat metabolic syndrome.
代谢综合征是现代世界主要的非传染性全球健康危害之一，其患病率不断上升。乙酰辅酶 A 羧化酶 2（ACC2）是参与该疾病表现的最重要的酶之一，因为它在脂肪酸代谢中起调节作用。
寻找新型有效的 ACC2 抑制剂作为治疗代谢综合征的潜在先导化合物。
在本研究中，对具有生物相关性的噻唑基苯醚衍生物作为 ACC2 抑制剂进行了二维定量构效关系（2D-QSAR）研究，以进行结构优化。计算了生理化学描述符，从而通过回归方程得出了观察到的和预测的活性之间的相关性。在所研究的情况下，获得了重要的描述符，即整分子的 logP 和取代基 1 的氢键供体数，用于设计新化合物，并从开发模型的回归方程中计算其预测的生物活性。通过与制备的 ACC2 受体进行对接研究进一步验证了这些化合物。
最有前途的预测先导化合物在取代的苯醚部分没有氢键供体基团，但整体亲脂性增加，与受体表现出优异的氨基酸结合亲和力，并显示出预测的抑制活性为 0.0025μM 和 0.0027μM。新设计的化合物经过新颖性检查。应用了 Lipinski 的五规则来检查它们的成药性，并且没有违反该规则。
本研究设计的化合物具有很大的潜力，可以产生口服有效的 ACC2 抑制剂来治疗代谢综合征。
