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Research Article CODEN: IJPRNK IMPACT FACTOR: 4.278 Gopinathan Narasimhan, IJPRBS, 2014; Volume 3(6): 402-415

ISSN: 2277-8713 IJPRBS

INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE INSILICO SCREENING OF 3,4 DIHYDROPYRIMIDONES AS CYCLOOXYGENASES-2 INHIBITORS GOPINATHAN NARASIMHAN, CHITRA KRISHNAN Department of Pharmaceutical Chemistry, Faculty of pharmacy, Sri Ramachandra University, porur, Chennai-116, Tamilnadu, India.

Accepted Date: 20/12/2014; Published Date: 27/12/2014

Abstract: Progress of the drug for the cure of inflammation is very fast in the most recent years. Turmoil in normal host defense systems is inflammation [1]. COX-2 is an oxido-reductase having a role in prostaglandin biosynthesis, inflammatory responses and in cardiovascular events. COX-2 has gained special focus on research since past few decades. In this study, Molecular modeling and docking analysis were used to predict and understand interactions between COX-2 and twenty four compounds of 3,4 dihydropyrimidones. 1CX2 atomic coordinates was retrieved from protein data bank (PDB). All ligands (Figure 1) were drawn by software chemsketch. Molegro virtual docker program that predicted interactions in terms of Dock score. The approach is applicable in engineering 3D structures of enzymatic models, and studying interactions of active site residues with ligands show that the three compounds: it is concluded that that 5-(1H-benzimidazol-2-yl)-4-(4-methoxyphenyl)-6-methyl-3,4dihydropyrimidin-2(1H)-thione, 5-(1H-benzimidazol-2-yl)-4-(4-hydroxyphenyl)-6-methyl-3,4dihydropyrimidin-2(1H)-one and 5-(1H-benzimidazol-2-yl)-4-(1H-indol-3-yl)-6-methyl-3,4dihydropyrimidin-2(1H)-thione could be a potent anti-inflammatory target molecule against COX-2 which may be worth for further clinical trials. Keywords: Anti-inflammation, COX-2, Molecular docking, Interactions Docking, Molegro virtual docker. Corresponding Author: MR. V. KRISHNA MURTHY NAIK Access Online On: www.ijprbs.com PAPER-QR CODE

How to Cite This Article: Gopinathan Narasimhan, IJPRBS, 2014; Volume 3(6): 402-415

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INTRODUCTION Defensive measure taken by the organism to get rid of the injurious stimuli is inflammation. For pain and inflammation, non-steroidal anti-inflammatory drugs (NSAIDs) were used Conventionally. NSAID inhibits cyclooxygenase (COX) which impair the production of prostaglandins a mediators of the inflammatory response and pain. The prostanoids had three main groups namely prostaglandins, prostacyclins, and thromboxanes which involved in the inflammatory response [2]. Formation of prostanoids is depended by cyclooxygenase (COX). COX-1, COX-2, and COX-3 are the isoenzymes of COX. COX-2 is invisible in normal tissues and induced during inflammation, hypoxia and many cancers but COX-1 is considered as constitutive enzyme, in most mammalian cells [ 3,4] . COX-1 and COX-2 is blocked by Classical NSAIDs such as aspirin. Inhibition of COX-1 there is reduction of inflammation but there is loss of lining of the stomach which cause stomach upset as well as ulceration and bleeding from the stomach and even the intestines [5]. Adverse drug reactions, case-control, and post-marketing surveillance studies have revealed that frequent use of NSAID associated with a relatively high incidence of adverse reactions in the GI tract due to the decrease in synthesis of the gastro protective prostaglandins PGE2 and PGI2, which are mainly produced by COX-1. To significantly reduce the GI toxicity and to obtain similar or better efficacy, which led to the development of selective COX-2 inhibitors. COX-2, an isoform of COX family, is highly persuaded in response to pro inflammatory stimuli, cytokines and consequential in exaggerated prostaglandin release. Importance of COX inhibitors in the clinical management of arthritis, inflammation and cancer a molecular docking studies on the COX-2 inhibitory activity of 3,4 dihydropyrimidones were carried out in view of the adverse events [6]. In the present study analogues are varied by different substitution to provide insight for future Endeavour's. The study also focuses on the comparison between the inhibitory potentials of the novel compounds on the COX-2. Docking various ligands to the protein of interest followed by scoring to determine the affinity of binding and to reveal the strength of interaction has also become increasingly important in the context of drug discovery. The molecular docking was performed for newly designed compounds against COX-2 protein, 1CX2 (PDB ID) with bound ligand 1-Phenylsulfonamide- 3trifluoromethyl-5-parabromophenylpyrazole (S58) extracted from protein data bank (PDB), by utilizing fast, exhaustive docking software Molegro virtualdocker. MATERIALS AND METHODS Molecular Docking study To study protein-ligand interactions X-ray crystallographic 3-dimensional structure of mouse Cyclooxygenase, 1CX2 atomic coordinates was retreived from protein data bank (PDB). 1CX2 is


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a Cyclooxygenase-2 (prostaglandin synthase-2 or COX-2) enzyme with EC Number: 1.14.99.1 classified under Oxido-reductase class of enzymes, complexed with a selective inhibitor S58 with 4 chains, with 3.0 A° resolution and 0.216 R-value respectively. Computational analysis was carried out on chain A of 1CX2. Twenty four molecules were selected to study the associated protein-ligands interactions. All ligands (Figure 1) were drawn by software chemsketch. Mol Dock Score scoring function was employed to predict the binding energy for active site residue-ligand interactions and docking studies computed for all ligands using Molegro virtual docker program that predicted interactions in terms of Dock score. All calculations were done on a Intel core I7 laptop with windows seven configuration. Docking was performed by using Molegro Virtual Docker (MVD) software package.. MVD performs flexible ligand docking, so the optimal geometry of the ligand will be determined during the docking. To obtain better potential binding sites in the cyclooxygenase-2 (PDB ID: 1CX2), a maximum of five cavities was detected using default parameters. RESULTS AND DISCUSSION Study of Ligand-Substrate Interaction The designed compounds were evaluated through docking techniques using MVD program. Designed compounds were docked on one of the crystal structures of cyclooxygenase II available through the RCSB Protein Data Bank (PDB entry 1CX2). The compounds were scored based on the minimized ligand protein complexes. New ligands were docked into the empty binding site of cyclooxygenase II in order to compare the binding affinity. S58 ligand with surrounding active site residues within 3.5 A°, hydrogen bonding interactions and the spatial orientation in binding pocket is given in Figure 3. The interacting residues surrounding the ligand within 3.5 A° distance are Leu 123, Arg44, Gln 42,Arg 469, Ser 471, Tyr122, Lys 468 and Asn 43 respectively. Virtual screening The twenty four ligand molecules having minimum energy were screened out as the possible inhibitors for COX-2 given in the (Table 1). 5-(1H-benzimidazol-2-yl)-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione had highest moldoc score of - 156.47.It had three hydrogen bonds. The Arg 469 of protein formed hydrogen bond with oxygen of methoxyl group of ligand. Second hydrogen bond is formed between Arg 44 of protein with oxygen of methoxyl group of ligand. The bond lengths were found to be 3.11 A◦. and 3.12 A◦. respectively. The third hydrogen bond was formed between Asn 43 of protein and NH of benzimidazole and bond length was found to be 3.17 A◦.. The urea derivative had mole dock score of - 130.66. It had two hydrogen bonds. Hydrogen bond was formed between Arg 44 of protein with oxygen of methoxyl group of ligand and the bond Available Online at www.ijprbs.com

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length was found to be 2.9 A◦. The another hydrogen bond was formed between Arg 469 of protein and oxygen of methoxyl group of ligand and the bond length was found to be 3.06 A◦. 5-(1H-benzimidazol-2-yl)-4-(1H-indol-3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione had molscore of - 148.71. It had two hydrogen bonds. Hydrogen bond was formed between Leu 472 amino acid of protein and NH of indole of the ligand. The bond length was found to be 2.58 A◦ . The another hydrogen bond was formed between Asn 43 amino acid of target and NH of benzimidazole of ligand. The bond length was found to be 2.98 A◦ . The Urea derivative had moledock score of -148.30 and two hydrogen bonds as that of its thione derivative. The hydrogen bond lengths were 2.50 A◦ and 2.89 A◦. 5-(1H-benzimidazol-2-yl)-4-(furan-2-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione had moldoc score of -140.548. It had one hydrogen bond formed between Cys 41 and NH of benzimidazole. The bond length was found to be 2.7 A◦. The urea derivative formed two hydrogen bond between Tyr 130 and NH of dihydropyrimidone near to phenyl substitution and carbonyl of dihydropyrimidone. The bond lengths were 2.93 A◦ and 2.78 A◦ respectively.5-(1Hbenzimidazol-2-yl)-4-(4-hydroxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one formed four hydrogen with molscore of -142.421.Glu 465 residue of protein formed the first hydrogen bond with hydroxyl group of ligand and its bond length was 2.7 A◦. The second hydrogen bond was formed between Arg 44 residue of protein with NH of benzimidazole, the bond length was found to be 3.3 A◦ . The other two hydrogen bonds were formed between Cys 41 of protein and carbonyl of dihydropyrimidone and NH of dihydropyrimidone near to phenyl substitution. The bond lengths were 2.5 A◦ and 3.2 A◦ respectively. The thione derivative had moldoc score of 129.218 which formed one hydrogen bond between Asp 125 of protein with hydroxyl of ligand and the bond length was found to be 2.64 A◦. 5-(1H-benzimidazol-2-yl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-onehad moldoc score of -138.913 with one hydrogen bond formed between Leu 472 residue of protein and NH of dihydropyrimidone near to methyl substitution and bond length was found to be 3.3 A◦.. The thione derivative had moldoc score of -126.01 kcal/mol formed one hydrogen bond between Asn 43 and NH of benzimidazole and the bond length was found to be 3.4 A◦. 5-(1Hbenzimidazol-2-yl)-4-(2-chlorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one had moldoc score of -133.997 kcal/mol formed two hydrogen bond. The hydrogen bond was formed between Cys 41 of protein with carbonyl and NH of dihydropyrimidone near to phenyl substitution, the bond length was found to be 3.2 A◦. The thione derivatives moldoc score was 129.412 kcal/mol with two hydrogen bond. Cys 41 formed hydrogen bond with NH of dihydropyrimidone owned bond length of 2.79 A◦. The other hydrogen bond was between Arg 44 and NH of benzimidazole with bond length of 3.4 A◦. 5-(1H-benzimidazol-2-yl)-4-(4-chlorophenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione owned the moldoc score of -133.651 with hydrogen bond formed between Asn 43 and NH of Available Online at www.ijprbs.com

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benzimidazole in the company of bond length 3.1 A◦. The urea derivative encompassed moldoc score was -128.68 kcal/mol along with one hydrogen bond between Asn 43 of protein and NH of benzimidazole owned bond length of 3.3 A◦. 5-(1H-benzimidazol-2-yl)-4-[4-(dimethylamino) phenyl]-6-methyl-3,4-dihydropyrimidine-2(1H)-one had moldoc score of -133.101 kcal/mol with two hydrogen bond. Cys 41 formed hydrogen bond with carbonyl and NH of dihydropyrimidone near to phenyl substitution with bond length of 2.7 A◦. Arg 44 formed hydrogen bond with NH of benzimidazole with bond length of 3.2 A◦. Thione derivatives owned moldoc score -129.41 kcal/mol with two hydrogen bonds. Arg 44 of protein formed hydrogen bond with NH of benzimidazole with bond length of 3.3 A◦. The hydrogen bond was formed between Cys 41 of protein and NH of dihydropyrimidone near to phenyl with bond length of 3.05 A◦. 5-(1H-benzimidazol-2-yl)-4-(4-hydroxy-3-methoxyphenyl)-6-methyl-3,4-dihydropyrimidine2(1H)-thione hold one hydrogen bond between Glu 87 of protein and hydroxyl of ligand with bond length of 2.90 A◦. The urea derivative formed three hydrogen bond. Asn 226 of protein formed hydrogen bond with oxygen of methoxyl of ligand which owned bond length of 3.13 A◦.The second hydrogen bond is formed between His 196 of protein and hydroxyl of ligand with bond length of 3.08 A◦. Ser 216 formed hydrogen bond with carbonyl of dihydropyrimidone which owned the bond length of 2.76 A◦.5-(1H-benzimidazol-2-yl)-4-(2-hydroxyphenyl)-6methyl-3,4-dihydropyrimidin-2(1H)-one formed two hydrogen bondwith moldoc score of 126.883 kcal/mol.Glu 87 formed hydrogen bond with hydroxyl group of ligand which owned bond length of 2.81 A◦. The other hydrogen bond was formed between Asn 112 and NH of dihydropyrimidone near to methyl substitution owned bond length of 2.61 A◦. The thione derivative formed two hydrogen bond with moldoc score -125.939 kcal/mol. Ile 108 formed two hydrogen bond with NH and N of benzimidazole which owned bond length were 2.71 A◦ and 2.97 A◦ respectively. 4-(4-aminophenyl)-5-(1H-benzimidazol-2-yl)-6-methyl-3,4-dihydropyrimidine-2(1H)-thione with moledoc score -125.283 kcal/mol owned one hydrogen bond. Asn 43 of protein formed hydrogen bond with N of benzimidazole owned bond length of 3.3 A◦. Its urea derivative formed one hydogen bond with moldoc score of -127.226 kcal/mol as that of its thione derivative owned bond length of 2.8 A◦.5-(1H-benzimidazol-2-yl)-4-(3-hydroxyphenyl)-6methyl-3,4-dihydropyrimidin-2(1H)-one with moledoc score -126.84 kcal/mol owned one hydrogen bond betwen Asn 44 of protein with hydroxyl group of ligand hold bond length of 2.68 A◦. The urea derivative formed on hydrogen bond between Asn43 of protein with NH of benzimidazole of ligand. Its bond length was 3.1 A◦ . The active site is present in A ring of the protein. The residue bind with the ligand is same as that of the standard compounds docked. The residues found in the active sites are as follows


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Lys 468, Gln 42, Cys 41, Glu 456, Asn 39, Glu 465, Gln 461, Asn 43, Asn 44, Ser 471, Arg 469, Arg 44, Tyr 22, Leu 472, Tyr 130 and Asp 125 . The ligands favorite attraction site as follows Cys41, Asn 43 and Arg 44. CONCLUSION By using computational approaches derivatives designed showed good interactions with COX-2 protein. 5-(1H-benzimidazol-2-yl)-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)thione had highest moldoc score of - 156.47 kcal/mol against 1CX2 (PDB ID) in docking analysis . Docking studies confirm that the main interaction of COX-2 inhibitors with enzyme is Hydrogen bond and Hydrophobic interactions with the binding pockets made by NH of benzimidazole and NN and Carbonyl dihydropyrimidones of the ligands. This information has potential implications to understand the mechanism of COX-2 related enzymatic inhibition reactions, and also applicable in the prediction of more effective inhibitors and engineering 3D structures of other enzymes as well.Hence, it is concluded that that 5-(1H-benzimidazol-2-yl)-4-(4-methoxyphenyl)6-methyl-3,4-dihydropyrimidin-2(1H)-thione , 5-(1H-benzimidazol-2-yl)-4-(4-hydroxyphenyl)-6methyl-3,4-dihydropyrimidin-2(1H)-one and 5-(1H-benzimidazol-2-yl)-4-(1H-indol-3-yl)-6methyl-3,4-dihydropyrimidin-2(1H)-thione could be a potent anti-inflammatory target molecule against COX-2 which may be worth for further clinical trials. In this study, computations on the interactions at the active site of COX-2 were carried out for twenty four ligands. In future, it may be necessary to explore the development of potential new anti-COX-2 drugs for treating cancer and inflammation. The present study shall help in rational drug design and synthesis of new selective COX-2 inhibitors with predetermined affinity and activity and provides valuable information for the understanding of interactions between COX-2 and the novel 3,4 dihydropyrimidones. ACKNOWLEDGMENTS The authors would like to express thanks Molegro ApS for providing a fully functional version of Molegro Virtual Docker software for a period of 30 days during which all the in-silico docking work was carried out. Conflict of interest: None declared Ethical approval: Not required NH

R

N H3C

NH N

X

Fig 1 General structure for ligand


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Table 1 Ligand with different substitution X = O or S R

N H

O H3C

NH2

N H3C

N H3C

CH3

OH CH3

OH

OH

O

Cl

OH O

Cl H3C


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Table 2 Moldoc score of ligand bind with target S.No 1

2

3

4

5

Name of the ligand 1cx2

Mol Dock Rerank Score score

Hbond energy

Hbond in A◦

NAG-661 [A]

-88.30

-8.76

Four

NAG_681 [A]

-90.59

S58_701 [A]

-145.747

5-(1H-benzimidazol-2-yl)4-(4-methoxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-156.479

5-(1H-benzimidazol-2-yl)-

-148.713

-79.43

-81.85

-107.038

-124.729

-119.135

-12.14

-8.53595

-6.59527

-3.53179


Residues

2.69

Lys 468

2.74

Gln 42

2.85

Cys 41

3.13

Glu 456

Six 2.64

Asn 39

2.99

Glu 465

3.25

Gln 461

3.47

Cys 41

2.66

Asn 43

3.17

Asn 44

Six 3.06

Ser 471

2.56

Arg 469

2.84

Arg 44

2.97

Asn 43

2.47

Tyr 22

3.10

Asn43

Three 3.11

Arg 469

3.12

Arg 44

3.17

Asn 43

Two

Leu 472 409

Research Article CODEN: IJPRNK IMPACT FACTOR: 4.278 Gopinathan Narasimhan, IJPRBS, 2014; Volume 3(6): 402-415 4-(1H-indol-3-yl)-6methyl-3,4dihydropyrimidin-2(1H)thione 6

7

8

9

2.58

Asn 43

2.98

5-(1H-benzimidazol-2-yl)4-(1H-indol-3-yl)-6methyl-3,4dihydropyrimidin-2(1H)one

-148.305

5-(1H-benzimidazol-2-yl)4-(furan-2-yl)-6-methyl3,4-dihydropyrimidin2(1H)-thione

-140.548

5-(1H-benzimidazol-2-yl)4-(4-hydroxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-142.421

5-(1H-benzimidazol-2-yl)6-methyl-4-phenyl-3,4dihydropyrimidin-2(1H)one


-118.474

-3.53907

Two

Leu 472

2.5

Asn 43

2.89

-112.911

-2.12788

One

Cys 41

2.7

-138.913

-112.016

-111.287

-6.51732

-3.98351

Four 2.7

Glu 465

3.3

Arg 44

2.5

Cys 41

3.2

Cys 41

One

Leu 472

3.3

10 5-(1H-benzimidazol-2-yl)4-(furan-2-yl)-6-methyl3,4-dihydropyrimidin2(1H)-one

-137.42

11 5-(1H-benzimidazol-2-yl)4-(4-methoxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)-

-136.234

-106.943

-105.075

-1.65897

-5.21197


Two 2.93

Tyr 130

2.78

Tyr 130

Three 3.11

Arg 469

3.12

Arg 44 410

Research Article CODEN: IJPRNK IMPACT FACTOR: 4.278 Gopinathan Narasimhan, IJPRBS, 2014; Volume 3(6): 402-415 thione

ISSN: 2277-8713 IJPRBS 3.17

12 5-(1H-benzimidazol-2-yl)4-(2-chlorophenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-133.997

13 5-(1H-benzimidazol-2-yl)4-(4-chlorophenyl)-6methyl-3,4dihydropyrimidin-2(1H)thione

-133.651

14 5-(1H-benzimidazol-2-yl)4-[4(dimethylamino)phenyl]6-methyl-3,4dihydropyrimidine-2(1H)one

-133.101

15 5-(1H-benzimidazol-2-yl)4-(4-hydroxy-3methoxyphenyl)-6methyl-3,4dihydropyrimidine-2(1H)thione

-132.194

16 5-(1H-benzimidazol-2-yl)4-(4-methoxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-130.662

17 5-(1H-benzimidazol-2-yl)4-[4(dimethylamino)phenyl]6-methyl-3,4dihydropyrimidine-2(1H)thione

-130.633

-106.133

-94.0444

-3.71668

-4.32159

Asn 43

Two 3.2

Cys 41

2.4

Arg 44

One

Asn 43

3.3

-98.1997

-101.246

-4.40611

-2.5

Two 2.7

Cys 41

3.2

Arg 44

One

Asp 125

2.64

-86.2072

-80.4025

-3.80308

-3.05553


Two 2.63

Lys 468

2.56

Lys 468

Two

Arg 44

2.9

Arg 469

3.06

411

Research Article CODEN: IJPRNK IMPACT FACTOR: 4.278 Gopinathan Narasimhan, IJPRBS, 2014; Volume 3(6): 402-415 18 5-(1H-benzimidazol-2-yl)4-(2-chlorophenyl)-6methyl-3,4dihydropyrimidin-2(1H)thione

-129.412

19 5-(1H-benzimidazol-2-yl)4-(4-hydroxy-3methoxyphenyl)-6methyl-3,4dihydropyrimidine-2(1H)thione

-129.218

20 5-(1H-benzimidazol-2-yl)4-(4-chlorophenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-128.68

21 4-(4-aminophenyl)-5-(1H benzimidazol-2-yl)-6methyl-3,4dihydropyrimidin-2(1H)one

-127.226

22 5-(1H-benzimidazol-2-yl)4-(2-hydroxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-126.883

23 5-(1H-benzimidazol-2-yl)4-(3-hydroxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)one

-126.846

24 5-(1H-benzimidazol-2-yl)6-methyl-4-phenyl-3,4dihydropyrimidin-2(1H)-

-126.01

-90.9104

-101.164

-3.13985

-2.80554

ISSN: 2277-8713 IJPRBS Two 2.79

Cys 41

3.4

Arg 44

One

Asp 125

2.64

-102.184

-1.43366

One

Asn 43

3.3

-101.743

-86.427

-1.41787

-2.4724

Three 3.2

Cys 41

2.9

Cys 41

3.18

Arg 44

One 3.1

-99.7425

-102.666

-2.66832

-0.643991


Cys 41

One 2.68

Arg 44

One

Asn 43

3.4

412



thione 25 5-(1H-benzimidazol-2-yl)4-(2-hydroxyphenyl)-6methyl-3,4dihydropyrimidin-2(1H)thione

-125.939

26 4-(4-aminophenyl)-5-(1Hbenzimidazol-2-yl)-6methyl-3,4dihydropyrimidine-2(1H)thione

-125.283

27 5-(1H-benzimidazol-2-yl)6-methyl-4-phenyl-3,4dihydropyrimidin-2(1H)one

-119.819

-90.5306

-100.323

-2.5

-0.645818

One 2.72

Cys 41

One

Asn 43

3.3

-98.2888

-0.719596

Two 2.63

Lys 468

2.56

Lys 468

Fig 2 5-(1H-benzimidazol-2-yl)-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)thione bind with 1CX2


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Figure 3 5-(1H-benzimidazol-2-yl)-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)thione bind with 1CX2 in surface view.

Fig 4 S58_701 [A] bind to 1CX2


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