Kronenberger Thales, Asse Leonardo Rander, Wrenger Carsten, Trossini Gustavo Henrique Goulart, Honorio Kathia Maria, Maltarollo Vinicius Gonçalves
Unit for Drug Discovery, Departamento de Parasitologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo, SP 05508-000, Brazil.
Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627 - Pampulha, Belo Horizonte, MG 31270-901, Brazil.
Future Med Chem. 2017 Feb;9(2):135-151. doi: 10.4155/fmc-2016-0179. Epub 2017 Jan 27.
FabI is a key enzyme in the fatty acid metabolism of Gram-positive bacteria such as Staphylococcus aureus and is an established drug target for known antibiotics such as triclosan. However, due to increasing antibacterial resistance, there is an urgent demand for new drug discovery. Recently, aminopyridine derivatives have been proposed as promising competitive inhibitors of FabI.
In the present study, holographic structure-activity relationship (HQSAR) analyses were employed for determining structural contributions of a series containing 105 FabI inhibitors.
RESULTS & CONCLUSION: The final HQSAR model was robust and predictive according to statistical validation (q and r equal to 0.696 and 0.854, respectively) and could be further employed to generate fragment contribution maps. Then, final HQSAR model together with FabI active site information can be useful for designing novel bioactive ligands.
FabI是金黄色葡萄球菌等革兰氏阳性菌脂肪酸代谢中的关键酶，是三氯生等已知抗生素的既定药物靶点。然而，由于抗菌耐药性不断增加，迫切需要发现新的药物。最近，氨基吡啶衍生物已被提议作为有前景的FabI竞争性抑制剂。
在本研究中，采用全息结构-活性关系（HQSAR）分析来确定包含105种FabI抑制剂的系列的结构贡献。
根据统计验证（q和r分别等于0.696和0.854），最终的HQSAR模型稳健且具有预测性，可进一步用于生成片段贡献图。然后，最终的HQSAR模型与FabI活性位点信息可用于设计新型生物活性配体。
