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

Morya VK, Kumari S, Kim EK - Clin Proteomics (2012)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Engineering, Inha University, Incheon, Republic of Korea, 402-751. moryavivek@gmail.com.

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.

No MeSH data available.


Sequence alignment of Ketol acid reductoisomerase of Aspergillus with Ketol acid reductoisomerase of Oryza sativa.
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Figure 1: Sequence alignment of Ketol acid reductoisomerase of Aspergillus with Ketol acid reductoisomerase of Oryza sativa.

Mentions: Homology based model of 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 [16-18] with a resolution of 2.8 Å. The modeled structure was validated by UCLA server. The exact sequence similarity id about 32.19% in respect to template, therefore the sequence homology between template and subjected sequence have been analyzed by multiple sequence analysis using Clustal matrix, the results are shown in Figure 1. It was found that the KARI sequence of Aspergillus shows the conserved patches with template between 14-280 and 421-556 amino acid residues. The conserved sequences were subjected for the prediction of their functional properties. It was found to be the sequence from 14-280 belong with NADB_Rossmann protein superfamily (Rossmann-fold NAD(P)H/NAD(P)(+) binding (NADB) domain). The NADB domain is found in numerous dehydrogenases of metabolic pathways such as glycolysis, and many other redox enzymes. NAD binding involves numerous hydrogen-bonds and van der Waals contacts, in particular H-bonding of residues in a turn between the first strand and the subsequent helix of the Rossmann-fold topology. Characteristically, this turn exhibits a consensus binding pattern similar to GXGXXG, in which the first 2 glycines participate in NAD(P)-binding, and the third facilitates close packing of the helix to the beta-strand. Typically, proteins in this family contain a second domain in addition to the NADB domain, which is responsible for specifically binding a substrate and catalyzing a particular enzymatic reaction. amino acid residues between 421-556 was found to be conserved domain of IlvC superfamily enzymes. This domain is mainly associated with, catalytic domain, involved in catalysis of acetohydroxy acids to dihydroxy valerates conversion. This reaction is the second in the synthetic pathway of the essential branched side chain amino acids valine and isoleucine.


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

Morya VK, Kumari S, Kim EK - Clin Proteomics (2012)

Sequence alignment of Ketol acid reductoisomerase of Aspergillus with Ketol acid reductoisomerase of Oryza sativa.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3298717&req=5

Figure 1: Sequence alignment of Ketol acid reductoisomerase of Aspergillus with Ketol acid reductoisomerase of Oryza sativa.
Mentions: Homology based model of 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 [16-18] with a resolution of 2.8 Å. The modeled structure was validated by UCLA server. The exact sequence similarity id about 32.19% in respect to template, therefore the sequence homology between template and subjected sequence have been analyzed by multiple sequence analysis using Clustal matrix, the results are shown in Figure 1. It was found that the KARI sequence of Aspergillus shows the conserved patches with template between 14-280 and 421-556 amino acid residues. The conserved sequences were subjected for the prediction of their functional properties. It was found to be the sequence from 14-280 belong with NADB_Rossmann protein superfamily (Rossmann-fold NAD(P)H/NAD(P)(+) binding (NADB) domain). The NADB domain is found in numerous dehydrogenases of metabolic pathways such as glycolysis, and many other redox enzymes. NAD binding involves numerous hydrogen-bonds and van der Waals contacts, in particular H-bonding of residues in a turn between the first strand and the subsequent helix of the Rossmann-fold topology. Characteristically, this turn exhibits a consensus binding pattern similar to GXGXXG, in which the first 2 glycines participate in NAD(P)-binding, and the third facilitates close packing of the helix to the beta-strand. Typically, proteins in this family contain a second domain in addition to the NADB domain, which is responsible for specifically binding a substrate and catalyzing a particular enzymatic reaction. amino acid residues between 421-556 was found to be conserved domain of IlvC superfamily enzymes. This domain is mainly associated with, catalytic domain, involved in catalysis of acetohydroxy acids to dihydroxy valerates conversion. This reaction is the second in the synthetic pathway of the essential branched side chain amino acids valine and isoleucine.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological Engineering, Inha University, Incheon, Republic of Korea, 402-751. moryavivek@gmail.com.

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.

No MeSH data available.