Pharmacophore and docking-based hierarchical virtual screening for the designing of aldose reductase inhibitors: synthesis and biological evaluation
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- 作者：Bhawna Vyas ; Manjinder Singh ; Maninder Kaur ; Om Silakari…
- 关键词：Pharmacophore mapping ; Pharmacophore ; based 3D ; QSAR ; Docking analysis ; Aldose reductase (ALR2) ; Flavonoid derivatives ; Virtual screening ; Diabetic complications
- 刊名：Medicinal Chemistry Research
- 出版年：2016
- 出版时间：April 2016
- 年：2016
- 卷：25
- 期：4
- 页码：609-626
- 全文大小：1,574 KB
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Manjinder Singh (2)
Maninder Kaur (2)
Om Silakari (2)
Malkeet Singh Bahia (2)
Baldev Singh (1)
1. Department of Chemistry, Punjabi University, Patiala, Punjab, 147002, India
2. Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences, Drug Research Punjabi University, Patiala, Punjab, 147002, India - 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
- 出版者：Springer US
- ISSN：1554-8120
文摘
A set of 54 studied flavonoid inhibitors of aldose reductase (ALR2) enzyme has been utilized for pharmacophore modeling and 3D-QSAR analysis using “PHASE” program of Schrödinger software. The generated pharmacophore model (AADRR.1109) was challenged to screen “PHASE” database to identify new ALR2 inhibitors. The retrieved hits were employed for docking analysis and pharmacokinetic parameter calculation to obtain orally active molecules. To predict the activity of final retrieved hits, 3D-QSAR model was developed, and the best model was selected on the basis of various statistical parameters (R train 2 0.719; Q test 2 0.647 and SD 0.663). Totally five screened molecules which showed better enhanced predicted activity were synthesized and evaluated for in vitro ALR2 inhibitory activity. All tested molecules showed ALR2 inhibitory activity (IC50) below 40 µM. Additionally, the free radical scavenging potential of synthesized molecules was also determined which played a useful role to control the progression of diabetic complications. All molecules showed good antioxidant potential, thus the designed molecules, in future, could be explored to ameliorate the development of diabetic complications.