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Discovery of Novel GSK-3β Inhibitors Using Pharmacophore and Virtual Screening Studies

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Abstract

Glycogen synthase kinase-3β (GSK-3β) is a kinase family enzyme and an emerged target for the treatment of various diseases. A total of 23 structurally diverse flavonoid inhibitors were used to generate pharmacophore models using HypoGen algorithm. The hypotheses Hypo1 was considered as a best model which consists of three features: one hydrophobic and two aromatic ring features. The Hypo1 pharmacophore model was employed as a query to screen NCI and natural compound databases to discover novel potential lead compounds. In addition, molecular docking studies were carried out with 596 compounds from screening studies. NSC230353, NSC66454, NSC159593, and NSC156759 from NCI database and STOCK1N-81808, ZINC02159818, ZINC04042470, and ZINC72326235 from natural compound database were identified as potential GSK-3β inhibitors.

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Authors and Affiliations

  1. Department of Chemistry, St. Joseph’s College, Bharathidasan University, Tiruchirappalli, Tamilnadu, India

    Namachivayam Balakrishnan & Joseph Santhana Raj

  2. Department of Chemistry, Sathayabama University, Jeppiaar Nagar, Chennai, India

    Naresh Kandakatla

Authors
  1. Namachivayam Balakrishnan
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  2. Joseph Santhana Raj
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  3. Naresh Kandakatla
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Correspondence to Joseph Santhana Raj.

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The authors declare that there is no conflict of interests regarding the publication of this paper.

Electronic supplementary material

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Supplementary material 1

Table 1 provides statistical parameters and Table 2–7 provides docking score, H-bond interactions and length, amino acid residues of lead compounds (PDF 689 kb)

Supplementary material 2

Chemical structures of 23 training/test set compounds applied to pharmacophore generation (PPTX 319 kb)

Supplementary material 3

Hypo 1 mapped to (a) most active compound Flavopiridol (IC50 0.28 μM), and also mapped to (b) low active compound Naringin (IC50 100 μM) (PPTX 387 kb)

Supplementary material 4

The difference in costs between the HypoGen runs and Fischer’s randomization runs, 95 % confidence level selected (PPTX 85 kb)

Supplementary material 5

The Pharmacophore overlay of hit compounds a NSC230353 b NSC66454 c NSC159593 d NSC156759 e STOCK1N-81808 f ZINC02159818 g ZINC04042470 h ZINC72326235 (PPTX 1625 kb)

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Balakrishnan, N., Raj, J.S. & Kandakatla, N. Discovery of Novel GSK-3β Inhibitors Using Pharmacophore and Virtual Screening Studies. Interdiscip Sci Comput Life Sci 8, 303–311 (2016). https://doi.org/10.1007/s12539-015-0100-4

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  • DOI: https://doi.org/10.1007/s12539-015-0100-4

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