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Identification of lead BAY60-7550 analogues as potential inhibitors that utilize the hydrophobic groove in PDE2A: a molecular dynamics simulation study

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Abstract

The phosphodiesterase (PDE) family of proteins are important regulators of signal transduction, which they achieve by controlling the secondary messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). cAMP and cGMP are involved in many critical intracellular processes such as gene transcription, kinase activation, signal transduction in learning and memory, and channel function as secondary messengers. The involvement of PDEs in neuronal communication has made them important therapeutic targets. Considering the recent discovery that PDE2A inhibition can improve cognitive functioning, a combined molecular dynamics simulation and scoring and docking study was carried out to identify selective inhibitors of PDE2A that specifically interact with the recently discovered hydrophobic groove in PDE2A. Using the X-ray crystal structure of PDE2A (from PDB ID: 4HTX), we investigated the binding modes of a range of promising inhibitors based on the known PDE2A inhibitor BAY60-7550 to PDE2A.

The lead molecule showing highest MMPBSA binding energy with 2D and 3D binding pose in hydrophobic groove.

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Acknowledgements

JK thanks the CSIR for a doctoral research fellowship. TU thanks the UGC for a basic scientific research fellowship. We also thank Prof. B. Jayaram, IIT Delhi, for access to the supercomputing facility. We acknowledge the support provided by the BRAF at C-DAC, Pune, India, when we were carrying out MD simulations using computational resources at that facility.

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Authors and Affiliations

  1. Department of Chemistry, Jamia Millia Islamia, Central University, New Delhi, India, 110025

    Jitendra Kumar, Tarana Umar, Mohammad Mobashir & Nasimul Hoda

  2. Department of Chemistry, Aligarh Muslim University, Aligarh, UP, India

    Tasneem Kausar & Shahid M. Nayeem

Authors
  1. Jitendra Kumar
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  2. Tarana Umar
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  3. Tasneem Kausar
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  4. Mohammad Mobashir
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  5. Shahid M. Nayeem
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  6. Nasimul Hoda
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Corresponding authors

Correspondence to Shahid M. Nayeem or Nasimul Hoda.

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Kumar, J., Umar, T., Kausar, T. et al. Identification of lead BAY60-7550 analogues as potential inhibitors that utilize the hydrophobic groove in PDE2A: a molecular dynamics simulation study. J Mol Model 23, 7 (2017). https://doi.org/10.1007/s00894-016-3171-1

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  • DOI: https://doi.org/10.1007/s00894-016-3171-1

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