New insight into the In-Silico prediction and molecular docking of Giardia intestinalis protease resistance to nitroimidazole

Dashwa Langbang

doi:10.17485/ijst/v13i43.100

Abstract

Background/Objective. Giardia intestinalis is a flagella protozoan residing in human intestine causing diarrhea that affecting most common among the children. Usually metronidazole and nitroimidazole were used for the treatment of giardiasis worldwide. Pyruvate Ferredoxin oxidoreductase (PFeO) protease enzyme may play a role inactivation of these drugs that may lead to resistance. Studies regarding drug resistance are very less. Therefore, present study was carried out to predict the structure and characterize them structurally as well as functionally by using appropriate in-silico methods. Methods: The proteins sequences of wild type and mutant strain i.e. Pyruvate Ferredoxin oxidoreductase (PFeO) and Pyruvate flavodoxin oxidoreductase (PFIO) were retracted from the NCBI and aligned using ClustalW. Bioinformatic tools were carried out like molecular dynamics simulations and docking to understand the three-dimensional (3D) conformational structure and interaction behavior of mutant and wild types with the ligand. Findings: The wild complex maintained an approximate 4H-bonds during simulation while the mutant complex could hardly maintain single H-bond by the end of the simulation, suggesting that 4-nitroimidazole is highly stable in the wild complex. Since the compound occupies this binding site by making stable H-bond with key interacting residues, the function of mutant may be affected. For the very reason, the mutant may be resistant to the nitroimidazole. Applications: Molecular dynamic simulation and docking results have increased our understanding of resistance mechanisms and may also help for the design derivatives of nitroimidazole that inhibit protein function more efficiently. Keywords: Molecular dynamic simulation; Nitroimidazole resistance; Pyruvate Ferredoxin Oxidoreductase (PFeO) mutant type; Pyruvate Flavodoxin Oxidoreductase (PFIO) wild type; Giardia intestinalis

Highlights

Some of the studies abroad has been reported that clinical isolates of Giardia intestinalis have diverse levels of resistance against these nitro groups of drugs may be due to overexpressing some protease enzymes related to drug resistance [10,11,12,13]
It has been reported that the protease enzyme known as pyruvate ferredoxin oxidoreductase (PFeO) mutant type which is present in the Giardia showed resistance to metronidazole and nitroimidazole drugs by inactivating the activity of these particular drugs [14]
The metronidazole inactive oxide form enters the cell of Giardia through passive diffusion methods and inside mitochondria organelle of Giardia the nitrogen being converted to toxic radicals by reduced pyruvate-ferredoxin oxidoreductase enzyme (PFeO) mutant type [15,16]

Summary

Introduction

The metronidazole inactive oxide form enters the cell of Giardia through passive diffusion methods and inside mitochondria organelle of Giardia the nitrogen being converted to toxic radicals by reduced pyruvate-ferredoxin oxidoreductase enzyme (PFeO) mutant type [15,16]. This mutation in the gene of pyruvate ferredoxin oxidoreductase of G. intestinalis can able to decrease the protein binding affinity process which brings down the expression of the protease enzyme and its resistance to nitroimidazole and metronidazole

Methods

Results

Discussion

Conclusion