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Detailed atomistic molecular modeling of a potent type ΙΙ p38α inhibitor

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Abstract

The active site conservation among protein kinases makes it a real challenge to design selective inhibitors. In this regard, detailed understanding of structural features responsible for functional behavior of different protein kinases is an important challenge in structure-based drug design. Amino acid decomposition analysis (ADA) is a powerful method to recognize and evaluate possible binding loci (hot spots) in ligand–receptor interaction. These hot spots could be used as a tool to differentiate selectivity profiles among similar protein kinases. p38α is a prominent target in the development of new anti-inflammatory agents. Type ΙΙ p38α inhibitors bind to DFG-out conformation of p38α in its inactive form. We performed a computational approach including MD simulations and ab initio method to evaluate a type ΙΙ p38α inhibitor. MD simulation was used to evaluate the binding pattern between ligand and p38α active site residues. Penetration of ligand thorough lipid bilayer was assessed by MD simulation using DPPC as a lipid bilayer model. Further conformational analysis was applied to determine induced ligand conformational instability due to binding to the receptor. ADA provided interesting results for pharmacophore discrimination. According to obtained results, residues Asp168, Leu167, Met109 and Glu71 had most contribution in binding to ligand. Conformational analysis showed that diffusion of ligand through lipid bilayer is done almost in nearly optimum structure. The obtained results could reveal some information on molecular basis of p38α inhibition, while being in good agreement with proposed pharmacophore in the literature.

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Acknowledgments

Financial supports of this project by research council of Hamadan University of Medical Sciences are acknowledged.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran

    Seyed Ahmad Ebadi

  2. Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nima Razzaghi-Asl

  3. Drugs and Advanced Sciences Research Center, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran

    Nima Razzaghi-Asl

  4. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Mehdi Khoshneviszadeh & Ramin Miri

  5. Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Mehdi Khoshneviszadeh & Ramin Miri

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  1. Seyed Ahmad Ebadi
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Correspondence to Seyed Ahmad Ebadi.

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Ebadi, S.A., Razzaghi-Asl, N., Khoshneviszadeh, M. et al. Detailed atomistic molecular modeling of a potent type ΙΙ p38α inhibitor. Struct Chem 26, 1125–1137 (2015). https://doi.org/10.1007/s11224-015-0568-x

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