Homology modeling, molecular dynamics and atomic level interaction study of snake venom 5′ nucleotidase

Arafat, A. S. Y. and Arun, A. and Ilamathi, M. and Asha, J. and Sivashankari, P. R. and D'Souza, C. J. M. and Sivaramakrishnan, V. and Dhananjaya, B. L. (2014) Homology modeling, molecular dynamics and atomic level interaction study of snake venom 5′ nucleotidase. Journal of Molecular Modeling, 20. ISSN 0948-5023

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Abstract

Abstract 5′ Nucleotidase (5′ NUC) is a ubiquitously distributed enzyme known to be present in snake venoms (SV) that is responsible primarily for causing dysregulation of physiological homeostasis in humans by inducing anticoagulant effects and by inhibiting platelet aggregation. It is also known to act synergistically with other toxins to exert a more pronounced anti-coagulant effect during envenomation. Its structural and functional role is not yet ascertained clearly. The 3D structure of snake venom 5′ nucleotidase (SV-5′ NUC) is not yet known and was predicted by us for the first time using a comparative homology modeling approach using Demansia vestigiata protein sequence. The accuracy and stability of the predicted SV-5′ NUC structure were validated using several computational approaches. Key interactions of SV-5′ NUC were studied using experimental studies/molecular docking analysis of the inhibitors vanillin, vanillic acid and maltol. All these inhibitors were found to dock favorably following pharmacologically relevant absorption, distribution, metabolism and excretion (ADME) profiles. Further, atomic level docking interaction studies using inhibitors of the SV-5′ NUC active site revealed amino acid residues Y65 and T72 as important for inhibitor–(SV-5′ NUC) interactions. Our in silico analysis is in good agreement with experimental inhibition results of SV-5′ NUC with vanillin, vanillic acid and maltol. The present study should therefore play a guiding role in the experimental design of new SV-5′ NUC inhibitors for snake bite management. We also identified a few pharmacophoric features essential for SV-5′ NUC inhibitory activity that can be utilized further for the discovery of putative anti-venom agents of therapeutic value for snake bite management.

Item Type:	Article
Uncontrolled Keywords:	animal, Animals, chemical structure, chemistry, Molecular Structure, metabolism, molecular docking, snake venom, molecular dynamics, priority journal, genetics, molecular interaction, protein analysis, enzymology, article, validation study, amino acid, amino acid sequence, Secondary, snakebite, Ligands, Molecular Dynamics Simulation, protein binding, Amino Acid, Amino Acid Sequence, sequence homology, Sequence Homology, experimental study, Benzaldehydes, vanillin, accuracy, binding site, Snake Venoms, absorption, ligand, Protein Binding, Molecular Sequence Data, Binding Sites, molecular genetics, static electricity, Static Electricity, Protein Structure, protein tertiary structure, Tertiary, protein secondary structure, enzyme inhibitor, Protein Interaction Mapping, nucleotidase, molecular model, 5' nucleotidase, 5'-Nucleotidase, benzaldehyde derivative, Demansia, excretion, maltol, pyrone derivative, Pyrones, Rumex, vanillic acid, Vanillic Acid, venom
Subjects:	C Chemical Science > Biochemistry
Divisions:	Department of > Biochemistry
Depositing User:	Arshiya Kousar Library Assistant
Date Deposited:	13 Jun 2019 05:21
Last Modified:	09 Jul 2019 11:32
URI:	http://eprints.uni-mysore.ac.in/id/eprint/2935

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