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Comparative modeling and virtual screening for the identification of novel inhibitors for myo-inositol-1-phosphate synthase

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Abstract

Myo-inositol-1-phosphate (MIP) synthase is a key enzyme in the myo-inositol biosynthesis pathway. Disruption of the inositol signaling pathway is associated with bipolar disorders. Previous work suggested that MIP synthase could be an attractive target for the development of anti-bipolar drugs. Inhibition of this enzyme could possibly help in reducing the risk of a disease in patients. With this objective, three dimensional structure of the protein was modeled followed by the active site prediction. For the first time, computational studies were carried out to obtain structural insights into the interactive behavior of this enzyme with ligands. Virtual screening was carried out using FILTER, ROCS and EON modules of the OpenEye scientific software. Natural products from the ZINC database were used for the screening process. Resulting compounds were docked into active site of the target protein using FRED (Fast Rigid Exhaustive Docking) and GOLD (Genetic Optimization for Ligand Docking) docking programs. The analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a significant role in ligand binding. Four compounds are shortlisted and their binding assay analysis is underway.

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Acknowledgments

This work is supported by the Higher Education Commission (HEC) of Pakistan. The authors would also like to thank the OpenEye Scientific Software for providing the academic license.

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Authors and Affiliations

  1. National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, 45320, Pakistan

    Syed Sikander Azam, Sara Sarfaraz & Asma Abro

Authors
  1. Syed Sikander Azam
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  2. Sara Sarfaraz
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  3. Asma Abro
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Corresponding author

Correspondence to Syed Sikander Azam.

Electronic supplementary material

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Figure S1

Supplementary material 1 Ramachandran plot for the model built by MODELLER (TIFF 2729 kb)

Figure S2

Supplementary material 2 Verify3D plot for the five models generated by MODELLER indicating the better quality of model 2 (TIFF 1313 kb)

Supplementary material 3 Physicochemical Properties of MIP synthase through Expasy ProtParam tool (PDF 10 kb)

Supplementary material 4 Calculated secondary structure elements by ProFunc (PDF 9 kb)

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Azam, S.S., Sarfaraz, S. & Abro, A. Comparative modeling and virtual screening for the identification of novel inhibitors for myo-inositol-1-phosphate synthase. Mol Biol Rep 41, 5039–5052 (2014). https://doi.org/10.1007/s11033-014-3370-8

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  • DOI: https://doi.org/10.1007/s11033-014-3370-8

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