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

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.

Vanillin Analog – Vanillyl Mandelic Acid, a Novel Specific Inhibitor of Snake Venom 5′‐Nucleotidase

“…The involvement of N. naja venom 5′NUC in inducing anticoagulant effect was demonstrated by the use of specific inhibitor, vanillyl acid (VA) . Our recent molecular docking interaction studies of snake venom 5′NUC with various inhibitors showed that structural analog of vanillin and VA differentially interacted and inhibited . In this study, we checked VMA inhibitory action on venom 5′NUC belonging to three different families, and thus its use as a biochemical or pharmacological tool to evaluate the role of enzyme 5′NUC in snake envenomation strategies is exemplified.…”

“…Although it is widely accepted that 5′NUC plays an important role in snake envenomation strategies, apart from its hemostatic functions modulation, its other pharmacological effects are not well characterized . Several studies have used specific inhibitors of enzymes as a biochemical or pharmacological tool to characterize/or establish its mechanism of action .…”

Purification and characterization of a platelet aggregation inhibitor and anticoagulant Cc 5_NTase, CD 73‐like, from Cerastes cerastes venom

“…Structural characterization and binding site prediction of SV‐5′ NUC1 from Demansia vestigiata revealed a predicted site comprising amino acids Y 65 and T 72 , which seemed to be Y 67 and T 76 for Cc‐5′NTase. In fact, vanillyl mandelic acid forms hydrogen bond with Y 65 , whereas vanillic acid forms hydrogen bonds with Y 65 and T 72 . Vanillic and vanillyl mandelic acids seemed to interact with Y 67 and T 76 of Cc‐5′NTase.…”

Novel Fused 1h- Imidazo[1,2-B] Pyrazole Analogues as Anti-Inflammatory and Analgesic Agents With Their Molecular Docking Studies Against Cox-1 and Cox-2

“…3D structures of all possible stereoisomer forms of synthesized compounds (ligands) were generated using the Marvin sketch [30] software package and were MM2 optimized using Discovery Studio 3.5. The bioavailability of compounds 6a, 6b, 6c, 6d, 6e, 6f, 7a, 7b, 7c, 7d, 7e and 7f was assessed using ADME (Adsorption, Distribution, Metabolism Elimination) program [31].…”