MOLECULAR MODELING AND DOCKING BASED STUDIES OF NOVEL CHALCONE SKELETON BASED COMPOUNDS ON GLUCOSAMINE-6-PHOSPHATE SYNTHASE ENZYMEHTML Full Text
MOLECULAR MODELING AND DOCKING BASED STUDIES OF NOVEL CHALCONE SKELETON BASED COMPOUNDS ON GLUCOSAMINE-6-PHOSPHATE SYNTHASE ENZYME
- M. M. Prasada Rao *1, S. A. Rehaman 2 and Rajendra Prasad Yejella 3
Department of Pharmaceutical Sciences 1, Department of Pharmaceutical Chemistry 1, QIS college of Pharmacy, JNTUK, Kakinada- 533003. Andhra Pradesh, India.
Department of Pharmaceutical Chemistry 2, Nirmala college of Pharmacy, Mangalagir Andhra Pradesh, India.
Department of Pharmaceutical Chemistry 3, University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India
ABSTRACT: Glucosamine-6-phosphate synthase (G6PS) (EC 126.96.36.199), is an one of the drug target for the anti microbial species. Systemic anti bacterial and anti fungal infections are of the growing problems in contemporary medicines, however only limited anti bacterial agents are in clinical practice for selective action with low toxicity. Then there is an emergency need for more effective version of existing molecules as well as new potential target specific molecules. In this scenario, our present study is an attempt to find out specific molecules via in silico screening of novel chalcone based series of compounds targeting the glucosamine-6-phosphate synthase. Among the twenty five novel designed chalcones skeleton series of compounds, all of them have found to be successfully docking inside the active binding domain of G6PS target with a binding energy in a range of -7.35 to -9.99 Kcal/mol with predicted IC50 value range of 4.11 micro molar to 47.68 nano molar respectively
Glucosamine-6-phosphate synthase, chalcone, antimicrobial, docking, binding energy, Molecular Interactions
INTRODUCTION: L-Glutamine:d-fructose-6-phosphate amidotransferase, also known as glucosamine-6-phosphate synthase (GlcN6P synthase) 1 , Glucosamine-6-phosphate synthase (L-glutamine: D-fructose- 6-phosphate aminotransferase (GlmS,1 EC 188.8.131.52)) catalyzes the first step in hexosamine biosynthesis, converting D-fructose 6-phosphate (Fru-6-P) into D-glucosamine 6-phosphate (GlcN- 6-P) using glutamine as the ammonia source (Scheme-1).
GlcN-6-P is a precursor of uridine diphospho-N-acetylglucosamine from which other amino sugar-containing molecules are derived. One of these products, N-acetylglucosamine, is an important constituent of the peptido glycan layer of bacterial cell walls and fungal cell wall chitin.2 Role of GlcN6P synthase in bacteria, eukaryotic organisms, glucose metabolism related to diabetes, cancer, inflammation and ulcer has been reviewed elsewhere. 3
On the other hand, chalcone nucleus having prominent activities against microbes is known 4-6. A recent pharmaco-phore based studies by M.A. Baseer et al. 7 elucidated the potential of chalcone based compounds as promising drug like molecules. Therefore, it is of interest to design potential inhibitors using chalcone skeleton with appropriate modifications.
Software and programs:
Accelry’s Discovery studio ver 4.0 8 is utilized to visualize the ligand structures, receptors, hydrogen bonding network and to render images. Chemsktech was used to draw the ligand compounds. Autodock 4.0 9 is the primary docking program used in this work for the semi-flexible docking studies. Preparation of the ligands and protein receptors in pdbqt file and determination of the grid box size were carried out using Auto-Dock Tools version 1.5.6. Protocol used for performing protein and ligand preparation along with docking studies is same as followed elsewhere 10-12.
RESULTS AND DISCUSSION:
Docking and IC50 of the compounds with Glucosamine-6-phosphate synthase:
In order to know the binding energies involved in the protein ligand complex formation and to understand the molecular atomic level of interactions responsible for the target specific binding affinity of the compounds towards G6PS, we have performed the molecular docking studies for the present studied twenty compounds with the active binding site of G6PS protein target. Docking results have been are tabulated in Table 1.
TABLE 1: DOCKING RESULTS OF THE PRESENT STUDIED CHALCONE SERIES OF COMPOUNDS WITH GLUCOSAMINE 6-PHOSPHATE SYNTHASE
TABLE 2: DOCKING RESULTS OF SOME OF THE DRUG CANDIDATE FOR G6PS
|S.No||Ligand||Binding energy (Kcal/mol)||Reference|
|1.||Streptomycin||-5.72||Sumaiya et,al 13|
|2.||Glucose-6-phosphate||-5.9||Arora et al.14|
|3.||2,4,5-triarylimidazole derivative (a)||-7.37||
Ivan et.al, 15
|4.||2,4,5-triarylimidazole derivative (b)||-7.62|
|5.||2,4,5-triarylimidazole derivative (c)||-7.61|
|6.||N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid||-9.75||Banerjee et al. 16|
|7.||N-benzyl-2,2,2-trifluoroacetamide||-4.37||Balachandran et.al, 17|
All the twenty five compounds studied in this present work have shown to be successfully docking inside the active site of G6PS with a binding energy in a range of -7.66 to -10.16 Kcal/mol with predicted IC50 value range of 2.44 micro molar to 31.87 nano molar respectively. We have compared our docking results with some of the potent drug candidates for G6PS, as per the literature it is evident that Streptomycin and Glucose-6-phosphate were showing binding energy of -5.72 and -5.9 Kcal/mol respectively. Moreover, some other novel synthesized compound also shown potential antimicrobial activity targeting G6PS with a binding energy range of -4.37 to -9.75 kcal/mol Table 2 (see supplementary material). When these docking results of these potent drug candidates compared with our compounds docking results, it was identified that compound 7 is showing better binding energies than these controls by showing -10.23 Kcal/mol of binding energy with a far better IC50 value prediction of 31.87 nano molar respectively Table 1 (see supplementary material) for the G6PS target specific complex formation by forming hydrogen bonds with Trp74, Cys1, His77, Arg73, Thr76 residues repctively. a pi-pi and pi-cationic stacking with Trp74, His97, His86, His71 residues respectively (Fig. 1). Compounds interactions with the protein are tabulated in Table 3. Our in silico analysis revealed that these novel series of compounds have clearly demonstrated plausible high inhibitory potential for microbial targeting G6PS.
FIG.1: DOCKING SNAPSHOT OF (2E)-1-(2,4-DIFLUOROPHENYL)-3-(2-FLUORO-4-NITROPHENYL)PROP-2-EN-1-ONE (COMPOUND 07) AT THE ACTIVE BIMDING SITE OF GLUCOSAMINE 6-PHOSPHATE SYNTHASE
TABLE 3: MOLECULAR INTERACTIONS OF CHALCONE SERIES OF COMPOUNDS WITH GLUCOSAMINE 6-PHOSPHATE SYNTHASE
CONCLUSION: Our In silico studies provides a rationalization to the ability of present studied chalcones skeleton based series of compounds as a valuable small ligand molecule with strong binding affinity towards G6PS for plausible anti-microbial activity involving large value of negative binding energy by forming various interactions with the residues, all or some of which fall under catalytic active site important residues consolidating their complex’s thermodynamic stability. Moreover, predicted IC50 values further substantiated our hypothesis that these compounds have the potential to inhibit G6PS. The knowledge gained through this present study could be of high value for computational screening of target specific G6PS domain inhibitors by understanding the molecular interaction basis between ligand and receptor. The present investigated chalcone skeleton based series of compounds offers the possibility of expedient additional modifications that could give rise to lead structures with enhanced inhibitory activity and selectivity towards anti-microbial activity targeting drug targets like G6PS.All present studied compounds have been evaluated as good ADMET compiling compounds according to Lipinski's rule of five. The data have been presented in elsewhere.8
ACKNOWLEDGEMENT: Authors would like to thankful to Dr. S.A. Rahaman, Dr. Y. Rajendra Prasad Garu for sharing knowledge in developing the work and also to the QIS college of Pharmacy, ongole Principal and management throughout their encouragement for completion of work.
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How to cite this article:
Prasada Rao CH.M.M, Rehaman SA and Yejella RP: Molecular Modeling and Docking Based Studies of Novel Chalcone Skeleton Based Compounds on Glucosamine-6-Phosphate Synthase Enzyme. Int J Pharm Sci Res 2016; 7(5): 1956-66.doi: 10.13040/IJPSR.0975-8232.7(5).1956-66.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
CH.M.M. Prasada Rao*, S. A. Rehaman and Rajendra Prasad Yejella
Department of Pharmaceutical Sciences, QIS college of Pharmacy, JNTUK, Kakinada. AP, India
18 November, 2015
09 January, 2016
14 January, 2016
01 May 2016