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Use of molecular docking in the search for new anti-angiogenic agents

Hanane Boucherit

Laboratory of Applied Biochemistry. Department of Biochemistry and Cellular and Molecular Biology. Faculty of Natural and Life Sciences, Mentouri Brothers University, Algeria

Boussouf University Center, Mila, Algeria

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Nousseiba Zouaghi

Boussouf University Center, Mila, Algeria

Ziani Sara

Boussouf University Center, Mila, Algeria

Abdelouahab Chikhi

Laboratory of Applied Biochemistry. Department of Biochemistry and Cellular and Molecular Biology. Faculty of Natural and Life Sciences, Mentouri Brothers University, Algeria

Abderrahmane Bensegueni

Boussouf University Center, Mila, Algeria

Amina Merzoug

Laboratory of Applied Biochemistry. Department of Biochemistry and Cellular and Molecular Biology. Faculty of Natural and Life Sciences, Mentouri Brothers University, Algeria

DOI: 10.15761/CRR.1000123

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Abstract

Angiogenesis, the growth of new blood capillaries from preexisting vessels, is a crucial process in the development and spread of cancers. The inhibition of angiogenesis thus appears as a promising therapy for cancer. Methionine aminopeptidase type 2 (MetAP2) is a metallo-enzyme considered today as an attractive target for the fight against cancer because its inhibition blocks the process of angiogenesis and therefore tumor progression. The aim of this work is to study the inhibition of MetAP II by molecular docking methods in order to discover new anti-angiogenic agents.  FlexX is the molecular docking program used. Thus, this software allows predicting protein-inhibitor interactions. It was used to study the inhibition of 5JFR, a human MetAP II, by various molecules in order to discover the best inhibitors of this enzyme. The evaluation of the interaction energy of these inhibitors made it possible to identify those exhibiting the best inhibitory effect. These are compounds 6KP and A84, whose docking scores are -32.33 and -32.92 Kj/mol, respectively. The virtual screening of a similar collection of 370 of the compound 6KP and 139 of the compound A84 from PubChem revealed the compounds CID_66896495 and CID_11740546 as best inhibitors of MetAP II with an interaction energy equal to -40.27 KJ / mol for the first and -35.93 Kj / mol for the second. Finally, the Lipinski rule was performed to verify the pharmacokinetic properties of these two similar; they fit perfectly within the margin of the criteria imposed by Lipinski.

Key words

angiogenesis, molecular docking, FlexX, RMSD, methionine aminopéptidase II, Lipinski rule

Introduction

Cancer is a real public health problem, figure among the main causes of morbidity and mortality in the world. The surgery, radiotherapy and chemotherapy are the three main ways to fight against this disease. Despite the progress, these methods kill both cancer cells and healthy cells, which induce many side effects. For this, new research to treat without inducing too many side effects [1]. As well, to grow and sustain its nutritional needs, the tumor will need to develop its own vascularization. The predominant mechanism to which it will resort is angiogenesis, which consists in the formation of new blood vessels from other, pre-existing [2].

In recent years, angiogenesis is a current track research for the treatment, and a new approach revolutionary promising uses the anti-angiogenic properties of certain molecules to try to block the cancer in depriving tumors of the nutrients and oxygen they need to grow in order to make them die of hunger. The endothelial cells, specialized in the development of new blood vessels, are the target of most of the anti-angiogenic strategies [3].

Anti-angiogenic targeted therapies act on the environment of the tumor; by inhibiting the formation of new blood vessels, they slow down tumor growth and the development of metastases. It is therefore necessary to identify new therapeutic targets for developing anti-angiogenic agents, and thus be able to propose treatments adapted to each patient [4].

In this context, the methionine aminopeptidase Type 2 (MetAP2) has an attractive potential therapeutic target interesting to develop new anti-angiogenic agents [5,6]. The MetAP is a metalloprotease that cleaves N-terminal methionine during protein synthesis, one of the critical steps in the maturation of the protein [7] and a member of a protein family that regulates the growth of endothelial cells.

By maintaining it at the molecular level, biology is based on the interaction between a protein and its substrate in most biological reactions. Understanding its mode of operation and defining the residues involved is therefore essential to explain the mechanisms that influence the affinity between two molecules.

In pharmacology, it is then possible to study these interactions by a large number of docking programs (commercial or free) that can objectively, rapidly and efficiently search for the relative orientation of a very large number of ligands within a target protein (virtual screening), which is considerably easier to implement, cheaper and faster than using an experimental method [8]. In silico molecular docking methods have already proved to be very successful and at present they have become crucial steps in the design of new bioactive molecules.

Therefore, the objective of this work is to:

• Demonstrate the best inhibitor of human MetAP2 from the interactions energies calculated by FlexX software in order to propose in silico new inhibitors more powerful towards the therapeutic target in question;

• Computer simulation of a collection of similar inhibitors selected in the previous step, in order to propose new inhibitors more powerful toward the MetAP2. These results will probably help develop an effective therapeutic tool to fight cancer development.

Material and methods

Preparation of molecules for docking

The complex MetAP-inhibitor is downloaded from the PDB database (http://www.rcsb.org) by introducing its ID code. The Flex X software requires the 3D structure for both molecules (protein - ligand). In addition, Flex X does not need a prior preparation; it uses directly the .pdb format for the enzyme and the .sdf format for the downloaded ligand.

FlexX Program

We have worked with the FlexX program (https://www.biosolveit.de) in the latest version 2.2.0. 2016, it was installed in our microcomputers.

FlexX is a commercialized computer software, currently part of LeadIT and is among the most used in molecular modeling, it allows to simulate the interactions between proteins and ligands, which consists of proposing new inhibitors and to assist the development of molecules with therapeutic activity.

Choice of a crystallographic structure

We chose a good quality code for the human MetAP2 enzyme 5JFR. The characteristics of this enzyme are shown in Table 1.

Table 1. Main characteristics of code 5JFR

Code

Resolution (Å)

Factor R

Classification

Number of chains

Number of AA
per chain

Number of atoms
per chain

5JFR

1.6

0.17

3.4.11.18

1

369

2897

Inhibition of 5JFR by Flex X

The choice of 5JFR: Among the 20 MetAP2-inhibitor complexes we chose the 5JFR code for our study (Figure 1), due to its good RMSD and its good resolution compared to the other complexes found in the PDB. In addition, the presence of a co-crystallized inhibitor.

Figure 1. Structure of 5JFR.

Lipinski rule: Each possible drug must comply with several basic criteria, such as its low production cost, be soluble, stable, but must also comply with scales associated with its pharmacological properties of absorption, distribution, metabolism, Excretion and toxicity (ADME-T) [9]. This method is based essentially on Lipinski's rule 5 [10,11]:

  • A maximum molecular weight of 500 g / mol;
  • A maximum of 5 H-donor links;
  • A partition coefficient (logP) ≤ 5;
  • A maximum of 10 H-acceptor bonds;
  • Number of rotary functions ≤ 15.

Calculation of interactions "enzyme- similar": To study the interactions between the MetAP2 enzyme and the similar we use a specific PubChem library.

PubChem: is an American database of chemical molecules managed by the National Center for Biotechnology Information (NCBI), a branch of the National Medical Library of the United States under the authority of the National Institutes of Health (NIH). PubChem currently lists several million compounds whose structure and physicochemical properties are accessible free of charge via the internet (http://pubchem.ncbi.nlm.nih.gov). This bank was used to obtain the structural analogues of our ligands 6KP and A84 to a percentage of similarity 90% in order to dock them by our software to search among these compounds one that binds more strongly than the 6KP and A84 to our target human MetAP2 and propose it as a new, more effective inhibitor. After having introduced the name of the chosen inhibitor, the properties of the latter will appear.

Inhibition of 5JFR by Various Inhibitors

We have selected four compounds that act on human MetAP2. The structures of the inhibitors studied are represented in Table 2.

Table 2. Structure of inhibitors studied

N°

Inhibitor

Code

Name

1

6KP

7-fluoro-4-(5-methyl-3H-imidazo[4,5-b]pyridin- 6-yl)-2,4-dihydropyrazolo[4,3-b]indole

2

CID_66896495

5-N-(1H-indazol-6-yl)-4-N-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4,5-triamine

3

A84

2-[({2-[(1z)-3-(dimethylamino)prop-1-enyl]-4 fluorophenyl}sulfonyl)amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid

4

CID_11740546

2-[(2,4-difluorophenyl)sulfonylamino]-7-fluoronaphthalene-1-carboxylic
acid

Results and discussions

Study of the interactions involved in the inhibition of human MetAP2

Interaction 5JFR-Met 

To study the mode of interaction of different inhibitors with the active site of the human MetAP2 enzyme by molecular docking; we used the latest version of the FlexX program, it shows the hydrophobic interactions and the hydrogen bonds, these last are the most interesting among the weak bonds.

The amino acids of the active site of the enzyme MetAP2: According to the FlexX program, the amino acids of the active site are: His231, Asp251, Asp262, Asn329, His331, His339, Glu364, His382, Tyr383, Asp442, Tyr444, and Glu459.

Our approach consists firstly of studying the interaction with methionine (Met), substrate of the target.

Figure 2 shows the active site of MetAP2 complexed with Met. The substrate is well centered in the active site of the enzyme. The ligand is represented as "lines" of different colors, and the amino acids of the active site are represented in "wireframe".

Figure 2. Docking of Met in the active site of 5JFR.

The visualization of the results of the docking by FlexX shows that the Met forms with the active site of the MetAP2 8 hydrogen interactions represented in discontinuous dashes:

-Two hydrogen bridges are observed on the one hand between the carbonyl of the Met and the NH group of the residue His231 and on the other hand with a molecule of water (O……..H-N His231) and (O…….H-O-H747);

-Two hydrogen bridges are observed between the carbonyl of the Met and a molecule of water (O……..H-O-H747) and (O…….H-O-H747);

- A hydrogen bond is observed between the carbonyl of the Met and the Zn2 + ion present in the active site (O……..Zn480);

- Two hydrogen bridges are observed between two carbonyl functions of the residue Asp262 with the NH group of the Met (N-H……..OAsp262) and (N-H…….. O Asp262);

- A hydrogen bond is observed between the amine function of the Met and the carbonyl of the residue Asp251 (N-H……..O Asp251).

There are hydrophobic interactions stabilizing the Met with the residues Ile338, Phe219 His231 and the ion Zn480 shown in green lines depicted in Figure 3.

Figure 3. Representation of interaction formed with the substrate.

Interaction 5JFR-inhibitors

Docking : The docking of 20 molecules downloaded from the PDB with the .sdf format carrying different codes is carried out on the 5JFR crystallographic structure. We have considered interesting to test these inhibitors, and propose the best inhibitor of the enzyme MetAP2. The docking results are shown in Table 3.

Table 3. Docking results with the FlexX program

Number

Inhibitor Code

Score

Kj/mol

Structure

1

OVA

-10.51

Description: C:\Users\user\Desktop\OVA-270.png

2

FUG

    0.00

Description: C:\Users\user\Desktop\FUG-270.png

3

AO1

-22.17

Description: C:\Users\user\Desktop\AO1-270.png

4

AO2

-25.02

Description: C:\Users\user\Desktop\AO2-270.png

5

AO5

-24.43

Description: C:\Users\user\Desktop\AO5-270.png

6

A41

-32.07

Description: C:\Users\user\Desktop\A41-270.png

7

A75

-29.91

Description: C:\Users\user\Desktop\A75-270.png

8

A84

-32.92

Description: C:\Users\user\Desktop\A84-270.png

9

R20

-22.22

Description: C:\Users\user\Desktop\R20-270.png

10

F77

-30.63

Description: C:\Users\user\Desktop\F77-270.png

11

F79

-27,37

Description: C:\Users\user\Desktop\F79-270.png

12

A19

-28,07

Description: C:\Users\user\Desktop\A19-270.png

13

I96

-16,34

Description: C:\Users\user\Desktop\I96-270.png

14

52P

-20,59

Description: C:\Users\user\Desktop\52T-270.png

15

94A

-16,86

Description: C:\Users\user\Desktop\94A-270.png

16

57R

-15.2239

Description: C:\Users\user\Desktop\57R-270.png

17

6KP

-32,33

Description: C:\Users\user\Desktop\6KP-270.png

18

6KO

-23,71

Description: C:\Users\user\Desktop\6KO-270.png

19

6KN

-22,45

Description: C:\Users\user\Desktop\6KN-270.png

20

TN4

-10.17

Description: C:\Users\user\Desktop\TN4-270.png

It is useful to recall that among the 20 docked inhibitors, the compound 6KP (score = -32.33 Kj / mol) and compound A84 (score = -32.92 Kj / mol) with the best results (Table 4) present themselves as the Inhibitors the most powerful of the human MetAP2. For this we have chosen these compounds as a model in order to interpret their different interactions established with the enzyme MetAP2.

Table 4. Interaction energy of the best inhibitors

Ligand

Score Kj/mol

Match

Lipo

Ambig

Clash

Rot

#match

6KP

-32.33

-27.64

-11.39

-5.96

7.27

0.00

25

A84

-32.92

-30.47

-11.81

-4.75

3.12

5.60

20

Lipinski Rule : Before starting the study of the interactions between the enzyme MetAP2 and the 2 inhibitors 6KP and A84; we applied the Lipinski rule (Table 5). This rule describes the physicochemical properties of a compound tested.

Table 5. Molecular properties of inhibitors studied

N

Compounds

PM (g/mol)

nOH,NH

nO,N

ClogP

Nrotb

8

6KP

306.304

2

4

2.7

1

17

A84

432.51

2

7

2.2

7

PM: Molecular weight; nOH,NH: Number of H-bond donors; nO,N: Number of H-bond acceptors; clogP: LogP or calculated partition coefficient; nrotb: Number of rotable links.

The results of the table show that the two compounds 8 and 17 perfectly meet the criteria of the Lipinski rule. Both inhibitors are capable of exhibiting biological activity without having problems of oral absorption.

Visual analysis of the interactions "MetAP2 - inhibitors"

Interaction  5JFR-6KP : The visual analysis shows that the 6KP inhibitor is well placed in the active site of the enzyme MetAP2 (Figure 4). The complex is stabilized by the training of four hydrogen bonds:

Figure 4. Mode of binding of the 6KP inhibitor to the active site of 5JFR

- A hydrogen bond is observed between the amine function of the 6KP inhibitor and a water molecule present in the active site (N……..H-O-H834);

- A hydrogen bond is observed between the amine function of the 6KP inhibitor and a water molecule present in the active site (N……..H-O-H822);

- A hydrogen bridge is formed between the amine function of the 6KP inhibitor and a water molecule present in the active site (N……..H-O-H609);

- A hydrogen bridge is formed between the amine function of the 6KP inhibitor and a water molecule present in the active site (N……..H-O-H642).

Several hydrophobic interactions stabilizing the 6KP inhibitor; they are carried out with the residues Ile338 His382, His339, Pro220, Phe219, Tyr444, Ala414, Met384, Ile338 and His231. The following figure visualizes these interactions:

Interaction : 5JFR-A84 : The FlexX program helped to view the number and type of links involved in the 5JFR-A84 interaction. The complex is stabilized by six hydrogen bonds (Figure 5):

Figure 5. Method of binding inhibitor A84 with the active site of 5JFR

- A hydrogen bond is observed between the NH group of the inhibitor and the hydroxyl function of Tyr444 (N-H……..O-H-Tyr444);

- A hydrogen bond is observed between the carbonyl of the inhibitor A84 and the NH group of the residue Asn329 (O……..H-N-Asn329);

- Three hydrogen bonds between the carbonyl of the inhibitor A84 and the water molecules present in the active site (O….H-O-H642), (O….H-O-H609) and (O….H-O-H822);

- A hydrogen bridge between the carbonyl of the inhibitor A84 and the metal ion Mn2+ (O…….Mn2+).

Hydrophobic interactions stabilizing A84 with residues His339, Tyr444, Leu447, His231, Ala414, Ile338 and Met384.

Proposed new inhibitors of human MetAP2

Inhibition of the human MetAP2 by the similar of compound 6KP

In the aim of finding new more potent inhibitors of human MetAP2, we performed the molecular docking of a collection of 370 similar of the 6KP compound with 90% similarity. These chemical compounds are downloaded from the PubChem database. The results of docking by FlexX are presented in Table 6.

Table 6. The interaction energy values of the similar 6KP by FlexX

N

Inhibitor code

Score (Kj/mol)

N

Inhibitor code

Score (Kj/mol)

1

CID_60692209

-29.95

187

CID_91523782

-25.78

2

CID_60931616

-25.37

188

CID_90763912

-24.21

3

CID_65618114

-27.04

189

CID_90783106

-22.25

4

CID_65618518

-27.29

190

CID_91446673

-25.18

5

CID_66802281

-21.29

191

CID_76683822

-20.37

6

CID_66681148

-29.20

192

CID_73426341

-27.56

7

CID_66802416

-25.50

193

CID_89107435

-28.96

8

CID_66806570

-18.99

194

CID_73054826

-24.28

9

CID_66895607

-27.97

195

CID_71462984

-16.02

10

CID_66896495

-40.27

196

CID_71457622

-14.19

11

CID_67185223

-26.12

197

CID_73055705

-22.87

12

CID_67395425

-27.11

198

CID_71253882

-26.93

13

CID_67395981

-29.06

199

CID_71253683

-28.66

14

CID_67396135

-26.96

200

CID_71138132

-36.43

15

CID_67396548

-29.78

201

CID_70666195

-23.45

16

CID_67398150

-30.67

202

CID_69981294

-20.71

17

CID_67407477

-29.38

203

CID_69344609

-28.70

18

CID_67409220

-27.49

204

CID_69150294

-22.46

19

CID_67409331

-28.53

205

CID_68820816

-24.00

20

CID_67517105

-29.67

206

CID_69077400

-21.21

21

CID_67588149

-27.91

207

CID_69149290

-22.65

22

CID_67918391

-26.63

208

CID_69150316

-19.74

23

CID_68063317

-16.69

209

CID_69150551

-19.30

24

CID_68241781

-29.82

210

CID_66778322

-20.75

25

CID_68260700

-29.89

211

CID_66778621

-27.28

26

CID_68260703

-21.59

212

CID_66789083

-32.73

27

CID_68296446

-31.36

213

CID_66778918

-26.93

28

CID_67395425

-27.11

214

CID_67076481

-23.00

29

CID_68306301

-24.52

215

CID_66985044

-21.29

30

CID_68349946

-29.84

216

CID_67320203

-22.71

31

CID_68643830

-26.28

217

CID_68035521

-21.12

32

CID_68643860

-24.51

218

CID_59503887

-20.84

33

CID_68686238

-28.29

219

CID_59548207

-28.51

34

CID_69569483

-28.19

220

CID_59784965

-26.09

35

CID_69978572

-25.69

221

CID_59784880

-20.69

36

CID_70721644

-27.45

222

CID_59834985

-28.02

37

CID_70723293

-22.10

223

CID_60688217

-23.72

38

CID_70727168

-25.61

224

CID_66574664

-30.75

39

CID_70732987

-27.27

225

CID_66619888

-16.65

40

CID_70745872

-33.07

226

CID_59279329

-25.39

41

CID_70753996

-29.70

227

CID_59320844

-20.60

42

CID_70882179

-27.81

228

CID_59299145

-29.45

43

CID_70981612

-33.83

229

CID_59408914

-26.13

44

CID_71118180

-36.85

230

CID_59320938

-18.51

45

CID_71118184

-31.47

231

CID_59410548

-14.40

46

CID_123459036

-32.89

232

CID_59410552

-9.53

47

CID_123468906

-22.26

233

CID_59410557

-13.43

48

CID_71135894

-33.81

234

CID_58494345

-24.65

49

CID_71195295

-30.65

235

CID_58494361

-26.62

50

CID_71196481

-19.30

236

CID_58395561

-17.31

51

CID_71196595

-35.24

237

CID_58494377

-20.98

52

CID_71197129

-36.82

238

CID_58494431

-24.84

53

CID_71224460

-33.99

239

CID_58494433

-19.96

54

CID_71666619

-35.72

240

CID_59023024

    0.00

55

CID_71721652

-24.80

241

CID_59053719

-24.13

56

CID_73333867

-33.05

242

CID_58335861

-24.36

57

CID_73425712

-26.53

243

CID_58335884

-26.20

58

CID_73425816

-26.50

244

CID_58382119

-21.48

59

CID_73426432

-32.13

245

CID_58394980

-17.80

60

CID_73426342

-19.97

246

CID_58395409

-22.00

61

CID_73426343

-27.12

247

CID_58395521

-22.32

62

CID_73426346

-33.34

248

CID_57917270

-21.09

63

CID_73426433

-29.44

249

CID_57803223

-28.83

64

CID_73426533

-25.84

250

CID_57917305

-23.05

65

CID_73426534

-23.67

251

CID_57917484

-22.27

66

CID_73426535

-24.88

252

CID_57990273

-31.92

67

CID_73426634

-22.53

253

CID_57917487

-21.92

68

CID_73426635

-23.33

254

CID_58212412

-22.07

69

CID_73426636

-16.61

255

CID_58164226

-21.09

70

CID_ 73426637

-24.64

256

CID_57803186

-25.50

71

CID_73426638

-21.77

257

CID_56971580

-26.38

72

CID_73426639

-24.65

258

CID_56971579

-23.36

73

CID_73426740

-15.55

259

CID_56971581

-21.67

74

CID_73426841

-19.98

360

CID_56971584

-24.57

75

CID_73426844

-26.58

261

CID_56971583

-24.69

76

CID_73426934

-25.84

262

CID_57477852

-20.78

77

CID_73426936

-25.53

263

CID_56911516

-26.63

78

CID_73426938

-22.62

264

CID_56914738

-25.91

79

CID_73427031

-27.55

265

CID_56964913

24.31

80

CID_73427128

-29.91

266

CID_56968277

-23.19

81

CID_73427131

-30.64

267

CID_56969870

-24.34

82

CID_73602825

-30.75

268

CID_56971364

-25.05

83

CID_73776964

-32.08

269

CID_53467204

-28.81

84

CID_73776965

-30.74

270

CID_56702964

-21.94

85

CID_73776966

-34.68

271

CID_56701575

-20.31

86

CID_73776969

-31.76

272

CID_56718837

-20.72

87

CID_73776982

-29.17

273

CID_56760588

-23.09

88

CID_73776983

-31.83

274

CID_56862202

-16.87

89

CID_73776985

-17.32

275

CID_56903702

-21.07

90

CID_73776986

-31.81

276

CID_56895085

-18.20

91

CID_73777001

-32.60

275

CID_56909010

-23.39

92

CID_73777002

-30.57

276

CID_56904736

-26.14

93

CID_73777003

-32.20

277

CID_56908944

-28.99

94

CID_73777041

-30.39

278

CID_53391408

-24.15

95

CID_73777093

-31.26

279

CID_53386318

-22.60

96

CID_73777094

-31.25

280

CID_53386266

-20.79

97

CID_73777095

-30.83

281

CID_53386265

-26.17

98

CID_73777096

-29.29

282

CID_53386212

-22.44

99

CID_73777097

-31.84

283

CID_53386262

-26.57

100

CID_73777117

-31.21

284

CID_53386065

-25.36

101

CID_73777120

-31.73

285

CID_53247380

-23.94

102

CID_73777141

-31.20

286

CID_53385608

-28.17

103

CID_73777142

-31.55

287

CID_53385610

-21.96

104

CID_73777143

-31.56

288

CID_53385694

-29.28

105

CID_73777160

-31.64

289

CID_52149343

-21.28

106

CID_73777180

-31.90

290

CID_52105283

-23.25

107

CID_73777182

-30.46

291

CID_52149466

-23.61

108

CID_73777203

-31.91

292

CID_52149467

-23.91

109

CID_73777204

-33.71

293

CID_52149468

-24.18

110

CID_73777206

-29.80

294

CID_52233282

-23.69

111

CID_73777207

-29.70

295

CID_50952457

-25.29

112

CID_73777231

-30.46

296

CID_50980221

-21.52

113

CID_73777229

-30.99

297

CID_52104075

-20.78

114

CID_73777233

-33.48

298

CID_52104076

-23.00

115

CID_73777254

-31.87

299

CID_89996909

-29.11

116

CID_73777255

-31.67

300

CID_89996980

-21.81

117

CID_73777256

-34.27

301

CID_89996985

-23.19

118

CID_73777257

-33.08

302

CID_89997015

-23.48

119

CID_73777276

-31.81

303

CID_89997016

-29.32

120

CID_73777277

-31.71

304

CID_89997020

-24.57

121

CID_73777278

-29.61

305

CID_89997025

-25.61

122

CID_73777279

-32.29

306

CID_89997096

-23.12

123

CID_75389929

-29.22

307

CID_90032792

-26.63

124

CID_76683823

-22.04

308

CID_90103748

-28.68

125

CID_76690840

-25.55

309

CID_90104859

-31.20

126

CID_77277816

-26.96

310

CID_90105333

-31.70

127

CID_78031119

-35.09

311

CID_90105351

-29.71

128

CID_78862342

-25.21

312

CID_90105393

-29.67

129

CID_85471419

-24.90

313

CID_90105584

-30.18

130

CID_85471421

-27.26

314

CID_90106563

-27.86

131

CID_85471819

-28.40

315

CID_90105777

-32.62

132

CID_87616463

-29.29

316

CID_90106134

-31.10

133

CID_87617017

-28.81

317

CID_90184906

-20.21

134

CID_89012982

-31.95

318

CID_90241411

-14.26

135

CID_89107436

-20.97

319

CID_90241443

-14.41

136

CID_89621494

-16.62

320

CID_90392446

-34.98

137

CID_89736646

-30.45

321

CID_90465087

-26.25

138

CID_89736652

-25.09

322

CID_95192271

-24.94

139

CID_89775969

-23.69

323

CID_95192272

-22.02

140

CID_89790507

-22.10

324

CID_95213677

-23.26

141

CID_89943353

-23.46

325

CID_95213678

-20.03

142

CID_89996896

-28.51

326

CID_95402502

-22.69

143

CID_95719490

-16.07

327

CID_95402503

-20.61

144

CID_95719491

-17.98

328

CID_123164286

-31.68

145

CID_97860688

-24.89

329

CID_123453257

-32.30

146

CID_97860689

-25.21

330

CID_101512968

-28.31

147

CID_6414464

-16,52

331

CID_16064939

-25,83

148

CID_6050889

-10,86

332

CID_15649470

-27,05

149

CID_6411753

   0,00

333

CID_20286888

-12,97

150

CID_6817311

-10,58

334

CID_15136425

-27,12

151

CID_6800914

  0,00

335

CID_20286932

-13,21

152

CID_6846696

-12,62

336

CID_20286895

-13,91

153

CID_10172014

-24,55

337

CID_20286979

-15,76

154

CID_9614625

-10,54

338

CID_20286892

-14,27

155

CID_10086264

-19,67

338

CID_20286983

-15,79

156

CID_10402605

-19,36

339

CID_20287054

-13,76

157

CID_11779677

-23,59

340

CID_20287064

-15,81

158

CID_10314503

-20,88

341

CID_20287021

-15,22

159

CID_15136426

-27,12

342

CID_22220154

-23,42

160

CID_22220163

-19,05

343

CID_4452867

-22,60

161

CID_24901328

-20,47

344

CID_44180844

-22,33

162

CID_24856686

-31,05

346

CID_43790603

-24,01

163

CID_22220135

-20,55

347

CID_44525865

-21,10

164

CID_25204149

  0,00

348

CID_44333475

-25,37

165

CID_25204074

-7,66

349

CID_46239371

-34,11

166

CID_29152203

-25,63

350

CID_45236119

-18,38

167

CID_28735488

-23,84

351

CID_46174150

-24,14

168

CID_25204073

-13,62

352

CID_44622425

-21,99

169

CID_39893609

-18,32

353

CID_46238768

-27,88

170

CID_39893341

-16,97

354

CID_46239373

-26,17

171

CID_29153292

-20,79

355

CID_46239669

-25,41

172

CID_31105950

-22,80

356

CID_46239576

-34,93

173

CID_29258203

-23,64

357

CID_46239374

-29,03

174

CID_39796586

-32,20

358

CID_46994822

-24,93

175

CID_39893609

-18,32

359

CID_46985083

-19,81

176

CID_42196258

-16,97

360

CID_46994487

-24,87

177

CID_39893341

-16,97

361

CID_46992554

-16,01

178

CID_42196256

-18,23

362

CID_46987457

-18,55

179

CID_43790603

-24,01

363

CID_46997872

-22,99

180

CID_44333475

-25,37

364

CID_49784288

-26,27

181

CID_44180844

-22,33

365

CID_49785079

-28,44

182

CID_43782655

-23,67

366

CID_49784291

-26,31

183

CID_43788097

-26,36

367

CID_49785081

-30,28

184

CID_49785830

-25,55

368

CID_49765102

-25,65

185

CID_49825728

-27,31

370

CID_49784289

-26,18

According to the results of this table, the similar number 10 (CID_66896495) has a score (-40.27 Kj / mol), lower than that of the inhibitor 6KP (-32.33 Kj / mol).

From Table 7, it is found that the similar CID_66896495 has a molecular weight of lower than 500g/mol and a LogP of less than 5; which indicates a better lipophilic character. Therefore, we can say that this similar respond the rule of Lipinski. We considered it useful to detail the interactions involved with the active site of MetAP2.

Table 7. Criteria of the Lipinski rule for compound CID_66896495

N

Compounds

PM (g/mol)

nOH,NH

nO,N

ClogP

Nrotb

10

CID_66896495

346.358

6

7

2.5

4

Visual analysis: The similar CID_66896495 forms with the active site of the MetAP2 seven hydrogen bonds:

- A hydrogen bridge is observed between the NH group of CID_66896495 and one of the ring nitrogen atoms of the His231 residue (N-H……..N His231);

- A hydrogen bond is formed between one of the nitrogen atoms of the ring of CID_66896495 and the NH group of the residue Asn329 (N……..H-N-Asn329);

- A hydrogen bond is observed between one of the nitrogen atoms of the ring of CID_66896495 and the NH group of the residue Asn329 (N……..H-N-Asn329);

- A hydrogen bridge is observed between the NH group of CID_66896495 and the carbonyl of the residue Asn329 (N-H……..O-Asn329);

- Three hydrogen bonds between one of the ring nitrogen atoms of CID_66896495 and the water molecules present in the active site (O….H-O-H642), (O….H-O-H609) and (O….H-O-H822).

In addition, this inhibitor establishes several hydrophobic interactions with the residues His339, Tyr444, His231 and Ile338 (Figure 6).

Figure 6. Representation of interactions formed by the similar CID_66896495

Inhibition of MetAP2 by similar to compound A84

Docking with FlexX, allowed us to calculate the energies of interaction of 139 similar of compound A84 from PubChem. These chemical compounds a percentage of similarity equal to 90%. The results are shown in the following table (Table 8).

Table 8. Docking results of the compounds of compound A84 with FlexX

N

Inhibitor code

Score(Kj/mol)

N

Inhibitor code

Score(Kj/mol)

1

CID_6102685

-19,85

71

CID_11597423

-19,23

2

CID_6102686

-20,01

72

CID_11597839

-18,12

3

CID_9997201

-19,13

73

CID_11604661

-16,22

4

CID_10067258

-23,55

74

CID_11627073

-17,81

5

CID_10043171

-22,24

75

CID_11613481

-21,56

6

CID_10023785

-23,50

76

CID_11633910

-17,62

7

CID_10246955

-21,38

77

CID_11633065

-17,75

8

CID_10316628

-22,08

78

CID_11597629

-14,01

9

CID_10427648

-22,42

79

CID_11633910

-17,62

10

CID_10452412

-23,66

80

CID_11634034

-18,28

11

CID_11503087

-19,09

81

CID_11641105

-20,50

12

CID_11503191

-14,68

82

CID_11670580

-15,00

13

CID_11510709

-13,49

83

CID_11634668

-14,02

14

CID_11510884

-16,36

84

CID_11691459

-14,07

15

CID_11511194

-16,24

85

CID_23644716

-20,64

16

CID_11517700

-19,11

86

CID_11723962

-21,47

17

CID_11517913

-21,30

87

CID_16102135

-20,36

18

CID_11533113

-16,87

88

CID_11719751

-17,32

19

CID_11540018

-18,54

89

CID_23647759

-19,55

20

CID_11546119

-14,97

90

CID_23647744

-15,89

21

CID_11546431

-20,56

91

CID_23647749

-13,56

22

CID_11554308

-15,28

92

CID_23647760

-20,41

23

CID_11561873

-17,74

93

CID_23647750

-21,93

24

CID_11568437

-18,69

94

CID_23647761

-20,25

25

CID_11569061

-18,86

95

CID_23647763

-19,32

26

CID_11569838

-22,18

96

CID_23647764

-18,00

27

CID_11573782

-20,84

97

CID_23647762

-18,95

28

CID_11576103

-18,97

98

CID_23647765

-17,28

29

CID_11576138

-17,39

99

CID_49823464

-18,00

30

CID_11576736

-20,93

100

CID_44413210

-21,46

31

CID_11577513

-21,14

101

CID_44413082

-23,82

32

CID_11583139

-20,51

102

CID_49823470

-19,48

33

CID_11583415

-19,47

103

CID_49823469

-17,35

34

CID_11583793

-19,55

104

CID_49823468

-18,80

35

CID_11590100

-21,99

105

CID_49823467

-23,85

36

CID_10472482

-34.38

106

CID_68863564

-32.77

37

CID_10473619

-34.29

107

CID_68863594

-21.80

38

CID_11494819

-30.58

108

CID_68863597

-21.22

39

CID_11496527

-20.10

109

CID_68863702

-31.19

40

CID_11518259

-17.25

110

CID_68863786

-16.88

41

CID_11518441

-22.92

111

CID_68863903

-30.44

42

CID_11539865

-26.92

112

CID_68863953

-30.62

43

CID_11540135

-24.92

113

CID_68863959

-30.60

44

CID_11561945

-21.49

114

CID_68864095

-29.53

45

CID_11577513

-31.13

115

CID_68864103

-29.69

46

CID_11641129

-28.21

116

CID_68864168

-34.45

47

CID_11650034

-24.92

117

CID_68864495

-29.94

48

CID_11688827

-30.93

118

CID_68864532

-18.73

49

CID_11705475

-30.82

119

CID_68864533

-18.73

50

CID_11725102

-35.80

120

CID_68864556

-27.68

51

CID_11726205

-35.81

121

CID_68864649

-18.01

52

CID_11740546

-35.93

122

CID_68864747

-29.90

53

CID_23647745

-28.40

123

CID_68864859

-18.31

54

CID_23647746

-28.37

124

CID_68865409

-32.57

55

CID_23647747

-28.90

125

CID_68865656

-30.90

56

CID_23647748

-29.33

126

CID_68865690

-30.94

57

CID_58534736

-25.69

127

CID_68866195

-29.72

58

CID_66692930

-28.06

128

CID_68866305

-30.14

59

CID_68862448

-20.40

129

CID_68866392

-29.78

60

CID_68862458

-18.01

130

CID_68866470

-26.86

61

CID_68862468

-30.32

131

CID_68866569

-30.62

62

CID_68862483

-25.57

132

CID_68866571

-30.42

63

CID_68862795

-30.70

133

CID_68978420

-31.39

64

CID_68863037

-25.46

134

CID_69705690

-31.43

65

CID_68863110

-27.73

135

CID_69708551

-31.48

66

CID_68963412

-29.15

136

CID_70640996

-25.84

67

CID_68863537

-35.42

137

CID_87605037

-28.27

68

CID_68863539

-19.20

138

CID_ 90971823

-28.78

69

CID_68863545

-33.48

139

CID_101846961

-29.90

70

CID_68863560

-30.59

 

 

 

According to the results of this table, the similar number 52 (CID_11740546) showed a score (-35.93 Kj / mol), lower than that of the inhibitor A84 (-32.92 KJ/mol). Table 9 shows that similar CID_ 11740546 studied perfectly meets the Lipinski rule.

Table 9. Criteria of the Lipinski rule for compound CID_11740546

N

Compound

PM

nOH,NH

nO,N

ClogP

Nrotb

1

CID_11740546

381.325

2

8

4.1

4

Visual analysis : Visual analysis shows that the similar CID_ 11740546 forms five hydrogen bonds with the active site of the MetAP2.

- Two hydrogen bridges are formed on the one hand between the carbonyl of CID_11740546 and the metal ion Mn2+ and on the other hand with a molecule of water (O……Mn2+502) and (O…….H-O-H642) ;

- Three hydrogen bonds are formed between the carbonyl of CID_11740546 and the water molecules (O………...H-O-H609), (O………...H-O-H642) and (O………...H-O-H822).

The visualization of the docking results shows that similar CID_11740546 forms with the active site of the MetAP2 several hydrophobic interactions with the residues His231, Ala414, Tyr444, His331, Met384, Leu447, Leu328, Ile338, His382 and His339. Figure 7 shows these interactions.

Figure 7. Representation of the interactions formed by the similar CID_11740546

Conclusion

The main objective of our study was to assist in the development of new inhibitors of methionine aminopeptidase II, a promising therapeutic target for the development of new anti-angiogenic drugs.

Our approach consisted in the first step of demonstrating the best inhibitor of MetAP2 among the 20 compounds derived from the PDB that we studied by FlexX. The two compounds 6KP and A84 being the best inhibitors, they have respectively the scores: -32.33 Kj / mol and -32.92 Kj / mol.

The second part was devoted to the search of new inhibitors of MetAP2. Computer simulation of a similar collection of 6KP and A84 inhibitors from PubChem; Allowed us to suggest compounds CID_66896495 and CID_11740546 as potential new inhibitors of MetAP2. Its energies of interaction less than those of 6KP and A84 and equal to -40.27 Kj / mol for the first and -35.93 Kj / mol for the second.

Finally, it is important to note that the two similar CID_66896495 and CID_11740546 tested by this study are consistent with the criteria imposed by the Lipinski rule, which are essential to allow the placing on the market of a possible drug.

To conclude, in the light of the results obtained in this work, which consists in the elucidation of the inhibition of the human MetAP2 by the molecular docking method in order to discover new anti-angiogenes, we propose the compounds CID_66896495 and CID_11740546 as potential new inhibitors of the enzyme.

References

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Editorial Information

Editor-in-Chief

Dung-Fang Lee
The University of Texas

Article Type

Research Article

Publication history

Received date: May 10, 2017
Accepted date: May 29, 2017
Published date: May 31, 2017

Copyright

© 2017 Boucherit H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Hanane Boucherit (2017) Use of molecular docking in the search for new anti-angiogenic agents. Cancer Rep Rev 1: DOI: 10.15761/CRR.1000123

Corresponding author

Hanane Boucherit

Laboratory of Applied Biochemistry. Department of Biochemistry and Cellular and Molecular Biology, Faculty of Natural and Life Sciences, Mentouri Brothers University, Algeria, Boussouf University Center, Mila, Algeria

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Figure 1. Structure of 5JFR.

Figure 2. Docking of Met in the active site of 5JFR.

Figure 3. Representation of interaction formed with the substrate.

Figure 4. Mode of binding of the 6KP inhibitor to the active site of 5JFR

Figure 5. Method of binding inhibitor A84 with the active site of 5JFR

Figure 6. Representation of interactions formed by the similar CID_66896495

Figure 7. Representation of the interactions formed by the similar CID_11740546

Table 1. Main characteristics of code 5JFR

Code

Resolution (Å)

Factor R

Classification

Number of chains

Number of AA
per chain

Number of atoms
per chain

5JFR

1.6

0.17

3.4.11.18

1

369

2897

Table 2. Structure of inhibitors studied

N°

Inhibitor

Code

Name

1

6KP

7-fluoro-4-(5-methyl-3H-imidazo[4,5-b]pyridin- 6-yl)-2,4-dihydropyrazolo[4,3-b]indole

2

CID_66896495

5-N-(1H-indazol-6-yl)-4-N-(1H-pyrazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4,5-triamine

3

A84

2-[({2-[(1z)-3-(dimethylamino)prop-1-enyl]-4 fluorophenyl}sulfonyl)amino]-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid

4

CID_11740546

2-[(2,4-difluorophenyl)sulfonylamino]-7-fluoronaphthalene-1-carboxylic
acid

Table 3. Docking results with the FlexX program

Number

Inhibitor Code

Score

Kj/mol

Structure

1

OVA

-10.51

Description: C:\Users\user\Desktop\OVA-270.png

2

FUG

    0.00

Description: C:\Users\user\Desktop\FUG-270.png

3

AO1

-22.17

Description: C:\Users\user\Desktop\AO1-270.png

4

AO2

-25.02

Description: C:\Users\user\Desktop\AO2-270.png

5

AO5

-24.43

Description: C:\Users\user\Desktop\AO5-270.png

6

A41

-32.07

Description: C:\Users\user\Desktop\A41-270.png

7

A75

-29.91

Description: C:\Users\user\Desktop\A75-270.png

8

A84

-32.92

Description: C:\Users\user\Desktop\A84-270.png

9

R20

-22.22

Description: C:\Users\user\Desktop\R20-270.png

10

F77

-30.63

Description: C:\Users\user\Desktop\F77-270.png

11

F79

-27,37

Description: C:\Users\user\Desktop\F79-270.png

12

A19

-28,07

Description: C:\Users\user\Desktop\A19-270.png

13

I96

-16,34

Description: C:\Users\user\Desktop\I96-270.png

14

52P

-20,59

Description: C:\Users\user\Desktop\52T-270.png

15

94A

-16,86

Description: C:\Users\user\Desktop\94A-270.png

16

57R

-15.2239

Description: C:\Users\user\Desktop\57R-270.png

17

6KP

-32,33

Description: C:\Users\user\Desktop\6KP-270.png

18

6KO

-23,71

Description: C:\Users\user\Desktop\6KO-270.png

19

6KN

-22,45

Description: C:\Users\user\Desktop\6KN-270.png

20

TN4

-10.17

Description: C:\Users\user\Desktop\TN4-270.png

Table 4. Interaction energy of the best inhibitors

Ligand

Score Kj/mol

Match

Lipo

Ambig

Clash

Rot

#match

6KP

-32.33

-27.64

-11.39

-5.96

7.27

0.00

25

A84

-32.92

-30.47

-11.81

-4.75

3.12

5.60

20

Table 5. Molecular properties of inhibitors studied

N

Compounds

PM (g/mol)

nOH,NH

nO,N

ClogP

Nrotb

8

6KP

306.304

2

4

2.7

1

17

A84

432.51

2

7

2.2

7

PM: Molecular weight; nOH,NH: Number of H-bond donors; nO,N: Number of H-bond acceptors; clogP: LogP or calculated partition coefficient; nrotb: Number of rotable links.

Table 6. The interaction energy values of the similar 6KP by FlexX

N

Inhibitor code

Score (Kj/mol)

N

Inhibitor code

Score (Kj/mol)

1

CID_60692209

-29.95

187

CID_91523782

-25.78

2

CID_60931616

-25.37

188

CID_90763912

-24.21

3

CID_65618114

-27.04

189

CID_90783106

-22.25

4

CID_65618518

-27.29

190

CID_91446673

-25.18

5

CID_66802281

-21.29

191

CID_76683822

-20.37

6

CID_66681148

-29.20

192

CID_73426341

-27.56

7

CID_66802416

-25.50

193

CID_89107435

-28.96

8

CID_66806570

-18.99

194

CID_73054826

-24.28

9

CID_66895607

-27.97

195

CID_71462984

-16.02

10

CID_66896495

-40.27

196

CID_71457622

-14.19

11

CID_67185223

-26.12

197

CID_73055705

-22.87

12

CID_67395425

-27.11

198

CID_71253882

-26.93

13

CID_67395981

-29.06

199

CID_71253683

-28.66

14

CID_67396135

-26.96

200

CID_71138132

-36.43

15

CID_67396548

-29.78

201

CID_70666195

-23.45

16

CID_67398150

-30.67

202

CID_69981294

-20.71

17

CID_67407477

-29.38

203

CID_69344609

-28.70

18

CID_67409220

-27.49

204

CID_69150294

-22.46

19

CID_67409331

-28.53

205

CID_68820816

-24.00

20

CID_67517105

-29.67

206

CID_69077400

-21.21

21

CID_67588149

-27.91

207

CID_69149290

-22.65

22

CID_67918391

-26.63

208

CID_69150316

-19.74

23

CID_68063317

-16.69

209

CID_69150551

-19.30

24

CID_68241781

-29.82

210

CID_66778322

-20.75

25

CID_68260700

-29.89

211

CID_66778621

-27.28

26

CID_68260703

-21.59

212

CID_66789083

-32.73

27

CID_68296446

-31.36

213

CID_66778918

-26.93

28

CID_67395425

-27.11

214

CID_67076481

-23.00

29

CID_68306301

-24.52

215

CID_66985044

-21.29

30

CID_68349946

-29.84

216

CID_67320203

-22.71

31

CID_68643830

-26.28

217

CID_68035521

-21.12

32

CID_68643860

-24.51

218

CID_59503887

-20.84

33

CID_68686238

-28.29

219

CID_59548207

-28.51

34

CID_69569483

-28.19

220

CID_59784965

-26.09

35

CID_69978572

-25.69

221

CID_59784880

-20.69

36

CID_70721644

-27.45

222

CID_59834985

-28.02

37

CID_70723293

-22.10

223

CID_60688217

-23.72

38

CID_70727168

-25.61

224

CID_66574664

-30.75

39

CID_70732987

-27.27

225

CID_66619888

-16.65

40

CID_70745872

-33.07

226

CID_59279329

-25.39

41

CID_70753996

-29.70

227

CID_59320844

-20.60

42

CID_70882179

-27.81

228

CID_59299145

-29.45

43

CID_70981612

-33.83

229

CID_59408914

-26.13

44

CID_71118180

-36.85

230

CID_59320938

-18.51

45

CID_71118184

-31.47

231

CID_59410548

-14.40

46

CID_123459036

-32.89

232

CID_59410552

-9.53

47

CID_123468906

-22.26

233

CID_59410557

-13.43

48

CID_71135894

-33.81

234

CID_58494345

-24.65

49

CID_71195295

-30.65

235

CID_58494361

-26.62

50

CID_71196481

-19.30

236

CID_58395561

-17.31

51

CID_71196595

-35.24

237

CID_58494377

-20.98

52

CID_71197129

-36.82

238

CID_58494431

-24.84

53

CID_71224460

-33.99

239

CID_58494433

-19.96

54

CID_71666619

-35.72

240

CID_59023024

    0.00

55

CID_71721652

-24.80

241

CID_59053719

-24.13

56

CID_73333867

-33.05

242

CID_58335861

-24.36

57

CID_73425712

-26.53

243

CID_58335884

-26.20

58

CID_73425816

-26.50

244

CID_58382119

-21.48

59

CID_73426432

-32.13

245

CID_58394980

-17.80

60

CID_73426342

-19.97

246

CID_58395409

-22.00

61

CID_73426343

-27.12

247

CID_58395521

-22.32

62

CID_73426346

-33.34

248

CID_57917270

-21.09

63

CID_73426433

-29.44

249

CID_57803223

-28.83

64

CID_73426533

-25.84

250

CID_57917305

-23.05

65

CID_73426534

-23.67

251

CID_57917484

-22.27

66

CID_73426535

-24.88

252

CID_57990273

-31.92

67

CID_73426634

-22.53

253

CID_57917487

-21.92

68

CID_73426635

-23.33

254

CID_58212412

-22.07

69

CID_73426636

-16.61

255

CID_58164226

-21.09

70

CID_ 73426637

-24.64

256

CID_57803186

-25.50

71

CID_73426638

-21.77

257

CID_56971580

-26.38

72

CID_73426639

-24.65

258

CID_56971579

-23.36

73

CID_73426740

-15.55

259

CID_56971581

-21.67

74

CID_73426841

-19.98

360

CID_56971584

-24.57

75

CID_73426844

-26.58

261

CID_56971583

-24.69

76

CID_73426934

-25.84

262

CID_57477852

-20.78

77

CID_73426936

-25.53

263

CID_56911516

-26.63

78

CID_73426938

-22.62

264

CID_56914738

-25.91

79

CID_73427031

-27.55

265

CID_56964913

24.31

80

CID_73427128

-29.91

266

CID_56968277

-23.19

81

CID_73427131

-30.64

267

CID_56969870

-24.34

82

CID_73602825

-30.75

268

CID_56971364

-25.05

83

CID_73776964

-32.08

269

CID_53467204

-28.81

84

CID_73776965

-30.74

270

CID_56702964

-21.94

85

CID_73776966

-34.68

271

CID_56701575

-20.31

86

CID_73776969

-31.76

272

CID_56718837

-20.72

87

CID_73776982

-29.17

273

CID_56760588

-23.09

88

CID_73776983

-31.83

274

CID_56862202

-16.87

89

CID_73776985

-17.32

275

CID_56903702

-21.07

90

CID_73776986

-31.81

276

CID_56895085

-18.20

91

CID_73777001

-32.60

275

CID_56909010

-23.39

92

CID_73777002

-30.57

276

CID_56904736

-26.14

93

CID_73777003

-32.20

277

CID_56908944

-28.99

94

CID_73777041

-30.39

278

CID_53391408

-24.15

95

CID_73777093

-31.26

279

CID_53386318

-22.60

96

CID_73777094

-31.25

280

CID_53386266

-20.79

97

CID_73777095

-30.83

281

CID_53386265

-26.17

98

CID_73777096

-29.29

282

CID_53386212

-22.44

99

CID_73777097

-31.84

283

CID_53386262

-26.57

100

CID_73777117

-31.21

284

CID_53386065

-25.36

101

CID_73777120

-31.73

285

CID_53247380

-23.94

102

CID_73777141

-31.20

286

CID_53385608

-28.17

103

CID_73777142

-31.55

287

CID_53385610

-21.96

104

CID_73777143

-31.56

288

CID_53385694

-29.28

105

CID_73777160

-31.64

289

CID_52149343

-21.28

106

CID_73777180

-31.90

290

CID_52105283

-23.25

107

CID_73777182

-30.46

291

CID_52149466

-23.61

108

CID_73777203

-31.91

292

CID_52149467

-23.91

109

CID_73777204

-33.71

293

CID_52149468

-24.18

110

CID_73777206

-29.80

294

CID_52233282

-23.69

111

CID_73777207

-29.70

295

CID_50952457

-25.29

112

CID_73777231

-30.46

296

CID_50980221

-21.52

113

CID_73777229

-30.99

297

CID_52104075

-20.78

114

CID_73777233

-33.48

298

CID_52104076

-23.00

115

CID_73777254

-31.87

299

CID_89996909

-29.11

116

CID_73777255

-31.67

300

CID_89996980

-21.81

117

CID_73777256

-34.27

301

CID_89996985

-23.19

118

CID_73777257

-33.08

302

CID_89997015

-23.48

119

CID_73777276

-31.81

303

CID_89997016

-29.32

120

CID_73777277

-31.71

304

CID_89997020

-24.57

121

CID_73777278

-29.61

305

CID_89997025

-25.61

122

CID_73777279

-32.29

306

CID_89997096

-23.12

123

CID_75389929

-29.22

307

CID_90032792

-26.63

124

CID_76683823

-22.04

308

CID_90103748

-28.68

125

CID_76690840

-25.55

309

CID_90104859

-31.20

126

CID_77277816

-26.96

310

CID_90105333

-31.70

127

CID_78031119

-35.09

311

CID_90105351

-29.71

128

CID_78862342

-25.21

312

CID_90105393

-29.67

129

CID_85471419

-24.90

313

CID_90105584

-30.18

130

CID_85471421

-27.26

314

CID_90106563

-27.86

131

CID_85471819

-28.40

315

CID_90105777

-32.62

132

CID_87616463

-29.29

316

CID_90106134

-31.10

133

CID_87617017

-28.81

317

CID_90184906

-20.21

134

CID_89012982

-31.95

318

CID_90241411

-14.26

135

CID_89107436

-20.97

319

CID_90241443

-14.41

136

CID_89621494

-16.62

320

CID_90392446

-34.98

137

CID_89736646

-30.45

321

CID_90465087

-26.25

138

CID_89736652

-25.09

322

CID_95192271

-24.94

139

CID_89775969

-23.69

323

CID_95192272

-22.02

140

CID_89790507

-22.10

324

CID_95213677

-23.26

141

CID_89943353

-23.46

325

CID_95213678

-20.03

142

CID_89996896

-28.51

326

CID_95402502

-22.69

143

CID_95719490

-16.07

327

CID_95402503

-20.61

144

CID_95719491

-17.98

328

CID_123164286

-31.68

145

CID_97860688

-24.89

329

CID_123453257

-32.30

146

CID_97860689

-25.21

330

CID_101512968

-28.31

147

CID_6414464

-16,52

331

CID_16064939

-25,83

148

CID_6050889

-10,86

332

CID_15649470

-27,05

149

CID_6411753

   0,00

333

CID_20286888

-12,97

150

CID_6817311

-10,58

334

CID_15136425

-27,12

151

CID_6800914

  0,00

335

CID_20286932

-13,21

152

CID_6846696

-12,62

336

CID_20286895

-13,91

153

CID_10172014

-24,55

337

CID_20286979

-15,76

154

CID_9614625

-10,54

338

CID_20286892

-14,27

155

CID_10086264

-19,67

338

CID_20286983

-15,79

156

CID_10402605

-19,36

339

CID_20287054

-13,76

157

CID_11779677

-23,59

340

CID_20287064

-15,81

158

CID_10314503

-20,88

341

CID_20287021

-15,22

159

CID_15136426

-27,12

342

CID_22220154

-23,42

160

CID_22220163

-19,05

343

CID_4452867

-22,60

161

CID_24901328

-20,47

344

CID_44180844

-22,33

162

CID_24856686

-31,05

346

CID_43790603

-24,01

163

CID_22220135

-20,55

347

CID_44525865

-21,10

164

CID_25204149

  0,00

348

CID_44333475

-25,37

165

CID_25204074

-7,66

349

CID_46239371

-34,11

166

CID_29152203

-25,63

350

CID_45236119

-18,38

167

CID_28735488

-23,84

351

CID_46174150

-24,14

168

CID_25204073

-13,62

352

CID_44622425

-21,99

169

CID_39893609

-18,32

353

CID_46238768

-27,88

170

CID_39893341

-16,97

354

CID_46239373

-26,17

171

CID_29153292

-20,79

355

CID_46239669

-25,41

172

CID_31105950

-22,80

356

CID_46239576

-34,93

173

CID_29258203

-23,64

357

CID_46239374

-29,03

174

CID_39796586

-32,20

358

CID_46994822

-24,93

175

CID_39893609

-18,32

359

CID_46985083

-19,81

176

CID_42196258

-16,97

360

CID_46994487

-24,87

177

CID_39893341

-16,97

361

CID_46992554

-16,01

178

CID_42196256

-18,23

362

CID_46987457

-18,55

179

CID_43790603

-24,01

363

CID_46997872

-22,99

180

CID_44333475

-25,37

364

CID_49784288

-26,27

181

CID_44180844

-22,33

365

CID_49785079

-28,44

182

CID_43782655

-23,67

366

CID_49784291

-26,31

183

CID_43788097

-26,36

367

CID_49785081

-30,28

184

CID_49785830

-25,55

368

CID_49765102

-25,65

185

CID_49825728

-27,31

370

CID_49784289

-26,18

Table 7. Criteria of the Lipinski rule for compound CID_66896495

N

Compounds

PM (g/mol)

nOH,NH

nO,N

ClogP

Nrotb

10

CID_66896495

346.358

6

7

2.5

4

Table 8. Docking results of the compounds of compound A84 with FlexX

N

Inhibitor code

Score(Kj/mol)

N

Inhibitor code

Score(Kj/mol)

1

CID_6102685

-19,85

71

CID_11597423

-19,23

2

CID_6102686

-20,01

72

CID_11597839

-18,12

3

CID_9997201

-19,13

73

CID_11604661

-16,22

4

CID_10067258

-23,55

74

CID_11627073

-17,81

5

CID_10043171

-22,24

75

CID_11613481

-21,56

6

CID_10023785

-23,50

76

CID_11633910

-17,62

7

CID_10246955

-21,38

77

CID_11633065

-17,75

8

CID_10316628

-22,08

78

CID_11597629

-14,01

9

CID_10427648

-22,42

79

CID_11633910

-17,62

10

CID_10452412

-23,66

80

CID_11634034

-18,28

11

CID_11503087

-19,09

81

CID_11641105

-20,50

12

CID_11503191

-14,68

82

CID_11670580

-15,00

13

CID_11510709

-13,49

83

CID_11634668

-14,02

14

CID_11510884

-16,36

84

CID_11691459

-14,07

15

CID_11511194

-16,24

85

CID_23644716

-20,64

16

CID_11517700

-19,11

86

CID_11723962

-21,47

17

CID_11517913

-21,30

87

CID_16102135

-20,36

18

CID_11533113

-16,87

88

CID_11719751

-17,32

19

CID_11540018

-18,54

89

CID_23647759

-19,55

20

CID_11546119

-14,97

90

CID_23647744

-15,89

21

CID_11546431

-20,56

91

CID_23647749

-13,56

22

CID_11554308

-15,28

92

CID_23647760

-20,41

23

CID_11561873

-17,74

93

CID_23647750

-21,93

24

CID_11568437

-18,69

94

CID_23647761

-20,25

25

CID_11569061

-18,86

95

CID_23647763

-19,32

26

CID_11569838

-22,18

96

CID_23647764

-18,00

27

CID_11573782

-20,84

97

CID_23647762

-18,95

28

CID_11576103

-18,97

98

CID_23647765

-17,28

29

CID_11576138

-17,39

99

CID_49823464

-18,00

30

CID_11576736

-20,93

100

CID_44413210

-21,46

31

CID_11577513

-21,14

101

CID_44413082

-23,82

32

CID_11583139

-20,51

102

CID_49823470

-19,48

33

CID_11583415

-19,47

103

CID_49823469

-17,35

34

CID_11583793

-19,55

104

CID_49823468

-18,80

35

CID_11590100

-21,99

105

CID_49823467

-23,85

36

CID_10472482

-34.38

106

CID_68863564

-32.77

37

CID_10473619

-34.29

107

CID_68863594

-21.80

38

CID_11494819

-30.58

108

CID_68863597

-21.22

39

CID_11496527

-20.10

109

CID_68863702

-31.19

40

CID_11518259

-17.25

110

CID_68863786

-16.88

41

CID_11518441

-22.92

111

CID_68863903

-30.44

42

CID_11539865

-26.92

112

CID_68863953

-30.62

43

CID_11540135

-24.92

113

CID_68863959

-30.60

44

CID_11561945

-21.49

114

CID_68864095

-29.53

45

CID_11577513

-31.13

115

CID_68864103

-29.69

46

CID_11641129

-28.21

116

CID_68864168

-34.45

47

CID_11650034

-24.92

117

CID_68864495

-29.94

48

CID_11688827

-30.93

118

CID_68864532

-18.73

49

CID_11705475

-30.82

119

CID_68864533

-18.73

50

CID_11725102

-35.80

120

CID_68864556

-27.68

51

CID_11726205

-35.81

121

CID_68864649

-18.01

52

CID_11740546

-35.93

122

CID_68864747

-29.90

53

CID_23647745

-28.40

123

CID_68864859

-18.31

54

CID_23647746

-28.37

124

CID_68865409

-32.57

55

CID_23647747

-28.90

125

CID_68865656

-30.90

56

CID_23647748

-29.33

126

CID_68865690

-30.94

57

CID_58534736

-25.69

127

CID_68866195

-29.72

58

CID_66692930

-28.06

128

CID_68866305

-30.14

59

CID_68862448

-20.40

129

CID_68866392

-29.78

60

CID_68862458

-18.01

130

CID_68866470

-26.86

61

CID_68862468

-30.32

131

CID_68866569

-30.62

62

CID_68862483

-25.57

132

CID_68866571

-30.42

63

CID_68862795

-30.70

133

CID_68978420

-31.39

64

CID_68863037

-25.46

134

CID_69705690

-31.43

65

CID_68863110

-27.73

135

CID_69708551

-31.48

66

CID_68963412

-29.15

136

CID_70640996

-25.84

67

CID_68863537

-35.42

137

CID_87605037

-28.27

68

CID_68863539

-19.20

138

CID_ 90971823

-28.78

69

CID_68863545

-33.48

139

CID_101846961

-29.90

70

CID_68863560

-30.59

 

 

 

Table 9. Criteria of the Lipinski rule for compound CID_11740546

N

Compound

PM

nOH,NH

nO,N

ClogP

Nrotb

1

CID_11740546

381.325

2

8

4.1

4