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Response surface methodology in docking study of small molecule BACE-1 inhibitors

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Abstract

Computational evaluation of ligand-receptor binding via docking strategy is a well established approach in structure-based drug design. This technique has been applied frequently in developing molecules of biological interest. However, any procedure would require an optimization set up to be more efficient, economic and time-saving. Advantages of modern statistical optimization methods over conventional one-factor-at-a-time studies have been well revealed. The optimization by experimental design provides a combination of factor levels simultaneously satisfying the requirements considered for each of the responses and factors. In this study, response surface method was applied to optimize the prominent factors (number of genetic algorithm runs, population size, maximum number of evaluations, torsion degrees for ligand and number of rotatable bonds in ligand) in AutoDock4.2-based binding study of small molecule β-secretase inhibitors as anti-alzheimer agents. Results revealed that a number of rotatable bonds in ligand and maximum number of docking evaluations were determinant variables affecting docking outputs. The interference between torsion degrees for ligand and number of genetic algorithm runs for docking procedure was found to be the significant interaction term in our model. Optimized docking outputs exhibited a high correlation with experimental fluorescence resonance energy transfer-based IC50s for β-secretase inhibitors (R2 = 0.9133).

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Acknowledgments

Financial supports of this project by Vice-chancellor Research of Shiraz University of Medical Sciences are acknowledged.

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Authors and Affiliations

  1. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran, PO Box 3288–71345

    Nima Razzaghi-Asl, Ahmad Ebadi, Najmeh Edraki, Ahmadreza Mehdipour, Sara Shahabipour & Ramin Miri

  2. Department of Medicinal Chemistry, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran, PO Box 1583–71345

    Nima Razzaghi-Asl, Ahmad Ebadi & Ramin Miri

  3. Computational Structural Biology Group, Max-Planck Institute of Biophysics, Max von Laue Strasse 3, Frankfurt am Main, 60438, Germany

    Ahmadreza Mehdipour

Authors
  1. Nima Razzaghi-Asl
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  2. Ahmad Ebadi
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  3. Najmeh Edraki
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  4. Ahmadreza Mehdipour
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  5. Sara Shahabipour
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  6. Ramin Miri
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Correspondence to Ramin Miri.

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Razzaghi-Asl, N., Ebadi, A., Edraki, N. et al. Response surface methodology in docking study of small molecule BACE-1 inhibitors. J Mol Model 18, 4567–4576 (2012). https://doi.org/10.1007/s00894-012-1424-1

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  • DOI: https://doi.org/10.1007/s00894-012-1424-1

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