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Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation

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ABSTRACT

Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. l-Asparagine (l-Asn) and l-glutamine (l-Gln) deamination plays crucial role in ALL treatment. Role of Erwinaze® (l-asparaginase from Erwinia chrysanthemi) in regulation of l-Asn and l-Gln has been confirmed by the experimental studies. Therapeutic research against ALL remained elusive with the lack of structural information on Erwinaze® enzyme. In this present study, homology model of the Erwinaze® was developed using MODELLER and the same was validated by various quality indexing tools. For the apo state enzyme and ligand bound state complexes molecular dynamics (MD) simulation was performed. The trajectory analysis showed the confirmational changes of structures in the dynamic system. Ligand binding mechanisms were studied using different docking tools to interpret the various ligand-receptor interactions and binding free energies. MD simulation of docked complex with l-Gln ligand substrate showed the defined structural folding with stable conformation over the l-Asn complex in dynamic environment. This research reports give much more information on structural and functional aspects of Erwinaze® with its ligands which may be useful in designing of effective therapeutics for ALL.

Electronic supplementary material: The online version of this article (doi:10.1007/s13205-016-0422-x) contains supplementary material, which is available to authorized users.

No MeSH data available.


Molecular docking results of Erwinaze® with ligand substrates a binding with l-Asn, b binding with l-Gln
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Fig2: Molecular docking results of Erwinaze® with ligand substrates a binding with l-Asn, b binding with l-Gln

Mentions: Summary of the binding energies by all the docking methods were described in Table 2. The mode of binding and cavity of ligands with receptor was visualized in PyMol molecular graphics viewer (Fig. 2). Cross checking of the modeled enzyme binding sites in docking was done with active site prediction tool (Ngan et al. 2012; Brenke et al. 2009). Pooled results exhibited matching of most of the residues, and thus, the binding sites used in docking approach were well defined (Supplementary material). As the exertion of biological activity of any drug is based on the binding between protein and ligand, present investigation results reveal that the nearly equal affinity of Erwinaze® towards both the ligands strongly supports Asparaginase and Glutaminase activities of the enzyme (Keating et al. 1993; Derst et al. 2000). Numerous adverse effects of l-Asparaginase usage have also been stated, distant from severe immunogenic reactions (Kwon et al. 2009).Table 2


Exploration of the binding modes of l -asparaginase complexed with its amino acid substrates by molecular docking, dynamics and simulation
Molecular docking results of Erwinaze® with ligand substrates a binding with l-Asn, b binding with l-Gln
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835421&req=5

Fig2: Molecular docking results of Erwinaze® with ligand substrates a binding with l-Asn, b binding with l-Gln
Mentions: Summary of the binding energies by all the docking methods were described in Table 2. The mode of binding and cavity of ligands with receptor was visualized in PyMol molecular graphics viewer (Fig. 2). Cross checking of the modeled enzyme binding sites in docking was done with active site prediction tool (Ngan et al. 2012; Brenke et al. 2009). Pooled results exhibited matching of most of the residues, and thus, the binding sites used in docking approach were well defined (Supplementary material). As the exertion of biological activity of any drug is based on the binding between protein and ligand, present investigation results reveal that the nearly equal affinity of Erwinaze® towards both the ligands strongly supports Asparaginase and Glutaminase activities of the enzyme (Keating et al. 1993; Derst et al. 2000). Numerous adverse effects of l-Asparaginase usage have also been stated, distant from severe immunogenic reactions (Kwon et al. 2009).Table 2

View Article: PubMed Central - PubMed

ABSTRACT

Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. l-Asparagine (l-Asn) and l-glutamine (l-Gln) deamination plays crucial role in ALL treatment. Role of Erwinaze® (l-asparaginase from Erwinia chrysanthemi) in regulation of l-Asn and l-Gln has been confirmed by the experimental studies. Therapeutic research against ALL remained elusive with the lack of structural information on Erwinaze® enzyme. In this present study, homology model of the Erwinaze® was developed using MODELLER and the same was validated by various quality indexing tools. For the apo state enzyme and ligand bound state complexes molecular dynamics (MD) simulation was performed. The trajectory analysis showed the confirmational changes of structures in the dynamic system. Ligand binding mechanisms were studied using different docking tools to interpret the various ligand-receptor interactions and binding free energies. MD simulation of docked complex with l-Gln ligand substrate showed the defined structural folding with stable conformation over the l-Asn complex in dynamic environment. This research reports give much more information on structural and functional aspects of Erwinaze® with its ligands which may be useful in designing of effective therapeutics for ALL.

Electronic supplementary material: The online version of this article (doi:10.1007/s13205-016-0422-x) contains supplementary material, which is available to authorized users.

No MeSH data available.