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Pharmacophore and docking-based hierarchical virtual screening for the designing of aldose reductase inhibitors: synthesis and biological evaluation

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Abstract

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 2train 0.719; Q 2test 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.

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Acknowledgments

Authors thank Dr. Ravikumar Muttineni (Application Scientist), Er. Anirban Banerjee (IT Consultant), and Mr. Raghu Rangaswamy from Schrodinger, Bangalore, for their constant scientific and technical support to handle Schrodinger software and work smoothly. Author, Bhawna Vyas, thank acknowledge Indian Council of Medical Research (ICMR), New Delhi, for providing Senior Research Fellowship (SRF); Grant No. 45/15/2011/BIF/BMS.

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  1. Department of Chemistry, Punjabi University, Patiala, Punjab, 147002, India

    Bhawna Vyas & Baldev Singh

  2. Molecular Modeling Lab (MML), Department of Pharmaceutical Sciences, Drug Research Punjabi University, Patiala, Punjab, 147002, India

    Manjinder Singh, Maninder Kaur, Om Silakari & Malkeet Singh Bahia

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  1. Bhawna Vyas
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  2. Manjinder Singh
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  6. Baldev Singh
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Correspondence to Baldev Singh.

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Vyas, B., Singh, M., Kaur, M. et al. Pharmacophore and docking-based hierarchical virtual screening for the designing of aldose reductase inhibitors: synthesis and biological evaluation. Med Chem Res 25, 609–626 (2016). https://doi.org/10.1007/s00044-016-1510-5

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