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Combining molecular dynamics simulation and ligand-receptor contacts analysis as a new approach for pharmacophore modeling: beta-secretase 1 and check point kinase 1 as case studies

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Abstract

Ligand-based pharmacophore modeling require relatively long lists of active compounds, while a pharmacophore based on a single ligand-receptor crystallographic structure is often promiscuous. These problems prompted us to combine molecular dynamics (MD) simulation with ligand-receptor contacts analysis as means to develop valid pharmacophore model(s). The particular ligand-receptor complex is allowed to perturb over a few nano-seconds using MD simulation. Subsequently, ligand-receptor contact points (≤2.5 Å) are identified. Ligand-receptor contacts maintained above certain threshold during molecular dynamics simulation are considered critical and used to guide pharmacophore development. We termed this method as Molecular-Dynamics Based Ligand-Receptor Contact Analysis. We implemented this new methodology to develop valid pharmacophore models for check point kinase 1 (Chk1) and beta-secretase 1 (BACE1) inhibitors as case studies. The resulting pharmacophore models were validated by receiver operating characteristic curved analysis against inhibitors obtained from CHEMBL database.

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Acknowledgments

The authors would like to thank IMAN1 Center—Jordan’s National Supercomputing Center—for providing us with the computational tools and high-performance computing system time to perform our experiments; the authors are deeply indebted to Eng. Zaid Abudayyeh from IMAN1 Center for his help in performing this project.

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Authors and Affiliations

  1. Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan

    Ma’mon M. Hatmal

  2. Department of Medical Analysis, Faculty of Allied Health Sciences, Zarqa Private University, Zarqa, Jordan

    Shadi Jaber

  3. Drug Discovery Unit, Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Jordan, Amman, Jordan

    Mutasem O. Taha

Authors
  1. Ma’mon M. Hatmal
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  2. Shadi Jaber
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  3. Mutasem O. Taha
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Correspondence to Mutasem O. Taha.

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Hatmal, M.M., Jaber, S. & Taha, M.O. Combining molecular dynamics simulation and ligand-receptor contacts analysis as a new approach for pharmacophore modeling: beta-secretase 1 and check point kinase 1 as case studies. J Comput Aided Mol Des 30, 1149–1163 (2016). https://doi.org/10.1007/s10822-016-9984-2

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  • DOI: https://doi.org/10.1007/s10822-016-9984-2

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