Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sect-67, SAS Nagar, Punjab 160 062, India.
Mol Divers. 2013 Feb;17(1):139-49. doi: 10.1007/s11030-013-9425-2. Epub 2013 Jan 19.
Acetyl-CoA carboxylase (ACC) is a crucial metabolic enzyme that plays a vital role in obesity-induced type 2 diabetes and fatty acid metabolism. To identify dual inhibitors of Acetyl-CoA carboxylase1 and Acetyl-CoA carboxylase2, a pharmacophore modelling approach has been employed. The best HypoGen pharmacophore model for ACC2 inhibitors (Hypo1_ACC2) consists of one hydrogen bond acceptor, one hydrophobic aliphatic and one hydrophobic aromatic feature, whereas the best pharmacophore (Hypo1_ACC1) for ACC1 consists of one additional hydrogen-bond donor (HBD) features. The best pharmacophore hypotheses were validated by various methods such as test set, decoy set and Cat-Scramble methodology. The validated pharmacophore models were used to screen several small-molecule databases, including Specs, NCI, ChemDiv and Natural product databases to identify the potential dual ACC inhibitors. The virtual hits were then subjected to several filters such as estimated [Formula: see text] value, quantitative estimation of drug-likeness and molecular docking analysis. Finally, three novel compounds with diverse scaffolds were selected as potential starting points for the design of novel dual ACC inhibitors.
乙酰辅酶 A 羧化酶（ACC）是一种关键的代谢酶，在肥胖引起的 2 型糖尿病和脂肪酸代谢中起着至关重要的作用。为了鉴定乙酰辅酶 A 羧化酶 1 和乙酰辅酶 A 羧化酶 2 的双重抑制剂，采用了药效团建模方法。针对 ACC2 抑制剂的最佳 HypoGen 药效团模型（Hypo1_ACC2）由一个氢键受体、一个疏水脂肪族和一个疏水芳族特征组成，而针对 ACC1 的最佳药效团（Hypo1_ACC1）则包含一个额外的氢键供体（HBD）特征。最佳药效团假说通过各种方法进行了验证，例如测试集、诱饵集和 Cat-Scramble 方法。验证后的药效团模型用于筛选多个小分子数据库，包括 Specs、NCI、ChemDiv 和天然产物数据库，以鉴定潜在的双重 ACC 抑制剂。然后，对虚拟命中物进行了多种筛选，例如估算的 [Formula: see text] 值、药物类似性的定量评估和分子对接分析。最后，选择了三个具有不同骨架的新型化合物作为设计新型双重 ACC 抑制剂的潜在起点。
