Computational modelling of nanotube delivery of anti-cancer drug into glutathione reductase enzyme

Saheen Shehnaz Begum,Ramesh Chandra Deka,Nand Kishor Gour,Dharitri Das

doi:10.1038/s41598-021-84006-1

Saheen Shehnaz Begum, Ramesh Chandra Deka + Show 2 more

Open Access

https://doi.org/10.1038/s41598-021-84006-1

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Journal: Scientific Reports	Publication Date: Mar 2, 2021
Citations: 9	License type: open-access

Affiliation: Tezpur University

Abstract

Density functional theory method combined with docking and molecular dynamics simulations are used to understand the interaction of carmustine with human glutathione reductase enzyme. The active site of the enzyme is evaluated by docking simulation is used for molecular dynamics simulation to deliver the carmustine molecule by (5,5) single walled carbon nanotube (SWCNT). Our model of carmustine in the active site of GR gives a negative binding energy that is further refined by QM/MM study in gas phase and solvent phase to confirm the stability of the drug molecule inside the active site. Once released from SWCNT, carmustine forms multiple polar and non-polar hydrogen bonding interactions with Tyr180, Phe209, Lys318, Ala319, Leu320, Leu321, Ile350, Thr352 and Val354 in the range of 2–4 Å. The SWCNT vehicle itself is held fix at its place due to multiple pi-pi stacking, pi-amide, pi-sigma interactions with the neighboring residues. These interactions in the range of 3–5 Å are crucial in holding the nanotube outside the drug binding region, hence, making an effective delivery. This study can be extended to envisage the potential applications of computational studies in the modification of known drugs to find newer targets and designing new and improved controlled drug delivery systems.

Highlights

Density functional theory method combined with docking and molecular dynamics simulations are used to understand the interaction of carmustine with human glutathione reductase enzyme
The decrease in radius of gyration (Rg) value for glutathione reductase (GR)-single walled carbon nanotube (SWCNT)-carmustine system than that of the GR protein suggests that the protein structure is more compact when the drug is bound to the active site of the GR, implying the high binding capacity of the drug to the protein
Molecular docking evaluates the active site for carmustine in Glutathione reductase environment

Summary

Introduction

Density functional theory method combined with docking and molecular dynamics simulations are used to understand the interaction of carmustine with human glutathione reductase enzyme. The docking of SWCNT with carmustine has been done on GR enzyme to develop the perspective of the binding site where the nanotube will land, with our focus on simulation of release of the drug from the endohedral cavity.

Results

Conclusion