COMPUTATIONAL DOCKING AND IN SILICO ANALYSIS OF POTENTIAL EFFLUX PUMP INHIBITOR PUNIGRATANE

Zumaana Rafiq,Rama Vaidyanathan,Saranya Sivaraj

doi:10.22159/ijpps.2018v10i3.21629

Abstract

Objective: Efflux-mediated resistance is a growing therapeutic complication as it reduces the efficacy of antibiotics. In gram-negative bacteria like E. coli and K. pneumoniae, this can be overcome with the help of efflux pump inhibitors (EPI) targeted at the transporter protein AcrB that plays a key role in binding to antibiotics. Our study focuses on the potential EPI Punigratane isolated from the rind of Punica granatum. Using computational docking analysis and in silico analysis, our aim is to determine whether Punigratane has the ability to interact and inhibit the AcrB pump and whether it has drug viability.Materials: Computational docking analyses were carried out using the online platforms Mcule and PatchDock. Drug-likeness and classification of Punigratane was predicted using online tools PreADMET and SuperPred. Admet SAR and Toxicity Checker at Mcule were used to predict ADME (absorption, distribution, metabolism, and excretion) and overt toxicity properties.Results: Punigratane was computationally docked with 57 AcrB crystal structures available at the PDB database to determine whether it could bind to the active site regions. It was found to bind in the periplasmic region close to the substrate bile acid where it is thought to bring about inhibition by steric hindrances. When docked with AcrB mutant (AcrB N109A), it was found to bind in the same periplasmic site as the substrates (EtBr, Rhodamine 6G, Ciprofloxacin, Bile acid) as well as the inhibitor (phenylalanine-arginine β-naphthylamide-PaβN). When docked in the active site of the inhibitor MBX2319, it was found to have a comparable docking score as well as the same hydrophobic interactions as the inhibitor. In silico analysis showed that Punigratane exhibited a drug-likeness to the inhibitor MBX2319 and that its drug classification is similar to antimicrobial agents. It was also found be a potential drug due to its intestinal absorption, increased bioavailability and non-toxic nature.Conclusion: Therefore our report shows that Punigratane could be a potential drug candidate that inhibits efflux activity by interacting and inhibiting the AcrB efflux pump.

Highlights

Antibiotic resistance, the silent pandemic, is taking the world by storm
Punigratane was computationally docked with 57 AcrB crystal structures available at the Protein Data Bank (PDB) database to determine whether it could bind to the active site regions
In silico analysis showed that Punigratane exhibited a drug-likeness to the inhibitor MBX2319 and that its drug classification is similar to antimicrobial agents

Summary

Introduction

Among the various factors that contribute to the resistant nature of bacteria, resistance via efflux pumps is a growing therapeutic complication. Efflux pumps are transport proteins that extrude toxic substances, including antibiotics, from the bacterial cells [1]. They confer resistance to a broad spectrum of antibiotics like macrolides, tetracyclines, and fluoroquinolones [2]. In E. coli and K. pneumoniae they are represented by the tripartite AcrAB-TolC system. AcrB is a transporter protein on the inner cell membrane that captures substrates in the cytoplasm or inner membrane of the cell envelope. AcrA is a periplasmic accessory protein that mediates the cooperation between AcrB and TolC [5, 6]

Methods

Results

Conclusion