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Identification of dual site inhibitors of tankyrase through virtual screening of protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models, molecular dynamics, and ADMET studies

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Abstract

Tankyrases are the group of poly (ADP-ribosyl) polymerases (PARPs) which are the attractive targets in various therapeutic areas such as cancer, antiviral, diabetes, and hormonal imbalance. The selective nature of tankyrase 1 and 2 inhibitors has created solid base to get dual site binders as they bind to induced adenosine binding site and nicotinamide binding site resulting in dual site inhibition. The present work describes the cheminformatics approach to find potential lead molecules as tankyrases dual site inhibitors through pharmacophore model by utilizing protein-ligand interaction fingerprints (PLIF) approach. The constructed pharmacophore model was used in virtually screening of ZINC and Interbioscreen database. Top ten hit molecules of virtual screening were subjected to molecular docking in order gain insights of key interactions at the adenosine and nicotinamide binding sites. The top hits were subjected to molecular dynamics simulation studies to gain deeper insights into probable mechanism of inhibition and stability of the complex. The top hit ZINC12973507 showed all the features required in key interactions at the active site of tankyrases and this hit molecule can be further explored as a potential drug candidate for dual site inhibition of tankyrases.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Acknowledgments

Authors are thankful to Dr. Zahid Zaheer, Principal, Y.B. Chavan College of Pharmacy, and Dr. Rafiq Zakaria Campus, Aurangabad 431001 (M.S.), India, for providing the laboratory facility. The authors SAA, HMA and AAA would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding through the Research Group Project No. RG-1439-010.

Funding

The authors SAA, HMA, and AAA received financial support from the Deanship of Scientific Research at King Saud University through the Research Group Project No. RG-1439-010.

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Authors and Affiliations

  1. Department of Pharmaceutical Medicinal Chemistry, Srinath College of Pharmacy, Aurangabad, M.S., 431136, India

    Manoj G. Damale

  2. Sinhgad Technical Education Society’s, Smt. Kashibai Navale College of Pharmacy, Kondhwa (Bk), Pune, India

    Rajesh Patil

  3. Department of Pharmaceutical Chemistry College of Pharmacy, King Saud University, PO Box 2454, Riyadh, 11451, Saudi Arabia

    Siddique Akber Ansari, Hamad M. Alkahtani & Abdulrahman A. Almehizia

  4. Dr. Rafiq Zakaria Campus, Y. B. Chavan College of Pharmacy, Rauza Baugh, Aurangabad, (MS), India

    Shahebaaz K. Pathan & Jaiprakash Sangshetti

  5. Department of Pharmaceutical Chemistry, Bhujbal Knowledge City, MET Institute of Pharmacy Adgaon, Nashik, India

    Santosh Chhajed

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  1. Manoj G. Damale
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  2. Rajesh Patil
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Correspondence to Rajesh Patil or Jaiprakash Sangshetti.

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Damale, M.G., Patil, R., Ansari, S.A. et al. Identification of dual site inhibitors of tankyrase through virtual screening of protein-ligand interaction fingerprint (PLIF)–derived pharmacophore models, molecular dynamics, and ADMET studies. Struct Chem 31, 769–779 (2020). https://doi.org/10.1007/s11224-019-01467-x

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