Virtual screening and evaluation of Ketol-Acid Reducto-Isomerase (KARI) as a putative drug target for Aspergillosis

Vivek K Morya,Shalini Kumari,Eun-Ki Kim

doi:10.1186/1559-0275-9-1

Abstract

Aspergillus is a leading causative agent for fungal morbidity and mortality in immuno-compromised patients. To identify a putative target to design or identify new antifungal drug, against Aspergillus is required. In our previous work, we have analyzed the various biochemical pathways, and we found Ketol Acid Reducto-Isomerase (KARI) an enzyme involves in the amino acid biosynthesis, could be a better target. This enzyme was found to be unique by comparing to host proteome through BLASTp analysis. A homology based model of KARI was generated by Swiss model server. The generated model had been validated by PROCHECK and WHAT IF programs. The Zinc library was generated within the limitation of the Lipinski rule of five, for docking study. Based on the dock-score six molecules have been studied for ADME/TOX analysis and subjected for pharmacophore model generation. The Zinc ID of the potential inhibitors is ZINC00720614, ZINC01068126, ZINC0923, ZINC02090678, ZINC00663057 and ZINC02284065 and found to be pharmacologically active agonist and antagonist of KARI. This study is an attempt to Insilco evaluation of the KARI as a drug target and the screened inhibitors could help in the development of the better drug against Aspergillus.

Highlights

Various reports from the past two decades point to the occurrence of invasive fungal infections have been greater than ever
Homology based model of Ketol acid reductoisomerase (KARI) was accomplished by swiss model server [17,18] and the structural homologue, which was used as a template for this model, is ketol acid reductoisomerase enzymes from rice, The PDB identifier 3fr8B [16,17,18] with a resolution of 2.8 Å
Comparative study of metabolome of the Aspergilli bestows the idea that essential enzymes can be targeted for antifungal drug designing [8], and 40 imperative proteins were identified from Aspergillus

Summary

Introduction

Various reports from the past two decades point to the occurrence of invasive fungal infections have been greater than ever. Aspergilli are a leading cause of fungal morbidity and mortality in immune compromised patients [1,2,3,4,5,6]. Accessible antifungal agents have quite a few downsides such as restricted potency and spectrum, non-optimal pharmacokinetics, severe resistance and drug-related toxicity. There is an emergent need to develop new antifungal drugs with a new chemical composition and novel mechanism of action [7]. Active efforts are being made by several international agencies and pharmaceutical majors to identify the drug targets and develop new drugs to treat these diseases effectively. To identify an antifungal drug targets for Aspergilli is required to develop new pharmaceuticals, to meet the challenge. Metabolic variations among organisms may be oppressive for the targets for pathogen such as Aspergilli

Methods

Results

Conclusion