MOLECULAR MODELING AND DOCKING BASED STUDIES OF NOVEL CHALCONE SKELETON BASED COMPOUNDS ON GLUCOSAMINE-6-PHOSPHATE SYNTHASE ENZYME

MOLECULAR MODELING AND DOCKING BASED STUDIES OF NOVEL CHALCONE SKELETON BASED COMPOUNDS ON GLUCOSAMINE-6-PHOSPHATE SYNTHASE ENZYME

1. 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 2.6.1.16), 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 2.6.1.16)) 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

SCHEME: 1

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.

Computation methods:

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

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.

REFERENCES:

1. Philippe Duranda, Be ́atrice Golinelli-Pimpaneau, Stephane Mouillerona Bernard et al: Highlights of glucosamine-6P synthase catalysis. 2008; 474 2: 302–317.
2. Stephen L. Bearne, Christian Blouin: Inhibition of Escherichia coli Glucosamine-6-phosphate Synthase by Reactive Intermediate Analogues the role of the 2-amino function in catalysis .The Journal Of Biological Chemistry, 2000; 275; 1:135–140.
3. Milewski S et al: Glucosamine-6-phosphate synthase--the multi-facets enzyme. Biochimica et Biophysica Acta 2002: 3; 1597(2):173-92.
4. M.M. Prasada Rao, V. Srinivasa Rao B, S.V. Jahnavi, Kishore.Ch: Synthesis and Antimicrobial Activity of some Novel Chalcones of Acetophenone and Benzaldehyde Derivatives. IJPI’s Journal of Medicinal Chemistry 2011; 1:6:11-15.
5. M. M. Prasada Rao, S. A. Rehaman, Y. Rajendra Prasad, G Eswara Rao: Design and Synthesis of 1-(3’,5’-bis trifluoromethyl phenyl)-3-(substituted phenyl)-2-propene-1-one as potent antifungal and antibacterial agents. Der Pharma Chemica, 2012; 4; 5:1997-2002.
6. M.M.Prasada Rao, Rehaman S.A Rajendra Prasad Yejella: Synthesis of novel 1-(2,4'-difluorophenyl)-3-(4"-aryl)-2-Propen-1-ones and their pharmacological Activities. World Journal of Pharmacy and Pharmaceutical Sciences 2014; 3 11:576-586.
7. A. Baseer et al: Synthesis, characterization, docking studies and bio-efficacy evaluation of novel chalcones. Journal of Chemical and Pharmaceutical Research, 2013, 5; 7:329-334.
8. http://accelrys.com/products/discovery-studio/visualization -download.php.
9. Goodsell DS, Morris GM and Olson AJ: Automated docking of flexible ligands: applications of AutoDock. journal of molecular recognition 1996;9;1:1-5.
10. Chennu Maruthi Malya Prasada Rao, Rajendra Prasad Yejella, Rehman Shaik Abdul& Syed Hussain Basha: Molecular docking based screening of novel designed chalcone series of compounds for their anti-cancer activity targeting EGFR kinase domain Bioinformation 2015:11(7): 322-329.
11. Reddy SV1, Reddy KT, Kumari VV, Basha SH.: Molecular docking and dynamic simulation studies evidenced plausible immunotherapeutic anticancer property by Withaferin A targeting indoleamine 2,3-dioxygenase.journal of biomolec ular and structural dynamics. 2015 11:1-15.
12. Syed Hussain Basha, Prakash Bethapudi, Majji Rambabu, Firoz et al: Anti-angiogenesis property by Quercetin compound targeting VEGFR2 elucidated in a computational approach. European Journal of Biotechnology and Bioscience 2014; 2; 6; 30-46.
13. Tabassum, T.H. Suresha Kumara, J.P. Jasinski etal: Synthesis Crystal Structure, ABTS Radical-Scavenging Activity, Antimicrobial and Docking Studies of Some Novel Quinoline Derivatives, Journal of Molecular Structure. 2014; 1070; 24: 10–20.
14. Arora Preeti, Rakesh Narang, Sonam Bhatia, et al: Synthesis, molecular docking and QSAR studies of 2, 4- disubstituted thiazoles as antimicrobial agents. J App Pharm Sci, 2015; 5; 02: 028-042.
15. Ivan H.R. Tomia, Ali H.R. Al-Darajia, Ahmed Mutanabbi Abdulaa: Synthesis, antimicrobial and docking study of three novel 2,4,5-triaryl imidazole derivatives. Journal of Saudi Chemical Society.2013( In Press)
16. Kamalika Banerjee, Utkarsh Gupta, Sanjay Gupta1, Gulshan Wadhwa, Reema Gabran : Molecular docking of glucosamine-6-phosphate synthase in Rhizopus oryzae .Bioinformation 2011; 7(6): 285-290.
17. Balachandran P. Saravana Kumar Y. Arun V. Duraipandiyan R.: Antimicrobial, antioxidant, cytotoxic and molecular docking properties of N-benzyl-2,2,2- trifluoro acetamide Applied Nano Sciences.2015;5:207–216.
    

    ---

    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.

    ---