Deniz Publication
Clinical Cancer Investigation Journal
ISSN Print: 2278-1668, Online: 2278-0513


Publisher: Deniz Publication
ARTICLE
Year: 2024   |   Volume: 13   |   Issue: 5   |   Page: 1-9     View issue

Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer


, , , , ,
  1. Pharmacochemistry Research Laboratory, Faculty of Biological-Chemical Sciences, University Autonomous of Campeche, Humberto Lanz Cárdenas s/n, Ex Hacienda Kalá, C.P. 24085, Campeche, Mexico. 

     
  2. Nutrition Laboratory, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico. 

  3. University Autonomous of Quintana Roo State, Campus Chetumal, Av Erik Paolo Martinez s/nesq. Av. 4 de marzo, Col. Magisterial, C.P. 77039, Méxic.

     
Abstract

Several studies indicate that cancer development is associated with angiogenesis, which may be conditioned for VEGFR-1, VEGFR-2, and VEGFR-3 expression. It is noteworthy that some drugs, such as axitinib, cediranib, regorafenib, and sorafenib, have been used to treat cancer. Nevertheless, some of these drugs can induce different adverse effects, such as thrombocytopenia and leukopenia. Analyzing these data, this study aimed to evaluate whether bicyclo analogs (1-27) could couple with VEGFR-1, VEGFR-2, and VEGFR-3, utilizing 3hng, 2oh4, 4sbj proteins, axitinib, cediranib, regorafenib, and sorafenib as controls in DockingServer software. Results indicate that bicyclo derivatives could interact at different sites of the 3hng, 2oh4, and 4sbj proteins surface compared to axitinib, cediranib, regorafenib, and sorafenib. Other report suggest that the inhibition constant (Ki) related to the interaction of bicylo 1 and 5 with the 3hng protein surface was lower compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs. Besides, the Ki for coupling of 4, 7, 8, 10, 12, and 15-22 with 2oh4 protein surface was lower compared with cabozatinib and cediranib drugs. Finally, the results for the interaction of bicyclo-analogs 4, 6-8, 10, 12, 13, 16, 18-21, 23, 24, and 26 were lower compared with axitinib and cediranib drugs. All these data suggest that bicyclo derivatives 1, 4, 6-8, 10, 12, 13, 15-24, and 26 could be good anticancer agents by modulating the VEGFR-1, VEGFR-2, and VEGFR-3 expression.

Keywords: Cancer, Byciclo, Axitinib, Cediranib, VEGFR-1

Introduction

There are statistical data indicating that cancer is a public health worldwide, resulting in a decrease in the quality of life of the population.[1-4] It noteworthy that there are some risk factors have been associated to involved in cancer development, such as hormone levels,[5, 6] smoking,[7] lifestyle,[8] alcohol,[9] dietary,[10] and others. In addition, some reports indicate that different types of cancers are associated with the angiogenesis process,[11-13] which is regulated by several biomolecules, such as vascular endothelial growth factor (VEGF), which plays an important role in cancer development.[14] It is noteworthy that vascular endothelial growth factor expression can be produced by hypoxia,[15] changes in pH,[16] and interleukine-6 activation.[17] This phenomenon may lead to interaction with some receptors involved in the endothelial cell surface, such as VEGF-R1, VEGF-R2, and VEGF-R3, which can be expressed in several cancers.[18-20] For example, a study showed that VEGF can stimulate the formation of new lymphatic vessels in patients with gastric cancer through  VEGFR-3 activation.[21]

 


Furthermore, a report display that VEGFR-3 expression was positively correlated with metastatic lymph nodes.[22] Other studies indicate that VEGFR-2 and VEGFR-3 are expressed in ovarian cancer patients using Western blott technique.[23] Other data suggest that both VEGFR-1 and VEGFR-2 could be expressed in bladder squamous cell carcinoma cell lines throuhg the Western immunoblotting method.[24] Furthermore, Nagano et al. (2019) disply that VEGFR-1 modulates epidermal growth factor receptor activity and can induce colon cancer cell growth by Western blot.[25]

 

On the other hand, some pharmacological strategies have been used to control cancer cell growth using some VEGFR-1, VEGFR-2, and VEGFR-3 receptor inhibitors; for example, a study indicated that axitinib can decrease metastatic renal cell carcinoma through VEGFR-1, VEGFR-2, and VEGFR-3 receptors inhibition.[26] Another study showed that Axitinib produces significant anticancer effects in epithelial ovarian cancer cells through inhibition of VEGF receptor signaling associated with cell proliferation, apoptosis, and migration.[27] Other studies display that regorafenib (a VEGF receptor non-selective antagonist) increases survival in patients with refractory metastatic colorectal cancer.[28] Besides, a report indicates that regorafenib combined with avelumab has antitumor activity in patients with biliary tract cancer;[29] however, a study showed that regorafenib can induce adaptive resistance of colorectal cancer cells via inhibition of the vascular endothelial growth factor receptor.[30] Furthermore, a study showed that the administration of sorafenib (a VEGFR-1, VEGFR-2, and VEGFR-3 inhibitor) can prolong survival in patients with advanced hepatocellular carcinoma.[31] Other data showed that may act as a VEGFR-1 receptor inhibitor using AG1-G1-Flt-1 cells.[32] All these data suggest that several anticancer drugs may act through VEGFR receptor inhibition; however, their interaction is not clear, perhaps this phenomenon could be due to experimental approaches used in the different studies performed. Analyzing these data, this study aimed to determine the possible interaction of twenty-seven bicyclo derivatives with VEGFR-1, VEGFR-2, and VEGFR-3 receptors using a theoretical model.

Materials and Methods

Figure 1 depicts the structure of twenty-seven bicyclo derivatives, which were utilized to ascertain if they may interact in the following ways with the VEGFR-1, VEGFR-2, and VEGFR-3 surface:

 

Figure 1. Chemical structure of bicyclo derivatives (1-27). Source: https://pubchem.ncbi.nlm.nih.gob

1 = 5-(4-methoxyphenyl)-2-(p-tolylsulfonyl)-2-aza-5-phosphabicyclo[2.2.1]heptane.

2 = 5-phenyl-2-(p-tolylsulfonyl)-2-aza-5-phosphabicyclo[2.2.1]heptane.

3  = (1S,2Z,4Z,7Z,9S)-bicyclo[7.2.0]undeca-2,4,7-triene-10,10,11,11-tetracarbonitrile.

4 = 1-(3-acetyl-1-bicyclo[1.1.1]pentanyl)ethanone.

5 = 1,2,3,4,5,6-hexachloro-7,7-dimethoxy-bicyclo[2.2.1]hept-2-ene.

6 = bicyclo[1.1.1]pentan-1-amine.

7 = 1-methoxybicyclo[2.2.2]oct-5-en-2-one.

8 = 2-isopropylsulfonylnorbornane.

9 = 2-(benzenesulfonyl)bicyclo[2.2.2]octane.

10 = 2,3-dibromonorbornane.

11 = 2,3-dichloronorbornane.

12 = 2-ethylnorbornane.

13 = 2-methylenenorbornane.

14 = 3,5,6-triphenyl-2,3,5,6-tetrazabicyclo[2.1.1]hex-1-ene.

15 = methyl N-[3-(benzyloxycarbonylamino)-1-bicyclo[1.1.1]pentanyl]-N-phenyl-carbamate.

16 = bicyclo[2.2.2]octane-1,4-diol.

17 = [3-(hydroxymethyl)-2-bicyclo[2.2.2]octanyl]methanol.

18 = bicyclo[2.2.1]hept-2-ene

19 = bicyclo[2.2.2]octan-2-ol.

20 = bicyclo[3.2.1]octan-6-one.

21 = bicyclo[3.2.1]octane-6,7-dione.

22 = bicyclo[3.3.1]nonan-3-one.

23 = norcaran-2-one.

24 = bicyclo[4.2.1]nona-2,4,7-triene.

25 = bicyclo[4.2.1]nonan-9-one.

26 = bicyclo[5.1.1]nonane-3,5-dione.

27 = bicyclo[5.3.1]undecan-9-one.

 

Ligand-protein complex

Coupling of bicyclo derivatives (1 to 30) with VEGFR1, VEGFR2, and VEGFR3 receptors, was determined using 2oh4,[33] 3hng,[34] and 4bsj[35] proteins as chemical tools. Furthermore, compounds such as axinib, cediranib, cabozatinib, and sorafinib were used as controls in the DockingServer program.[34]

Results and Discussion

Some theoretical methods, such as AutoDock, rDock, USFDock, and LeDock,[36] have been used to determine the interaction of different drugs with some biomolecules. Other data indicate that DockingServer can be used to evaluate the interaction of some anticancer drugs; for example, a theoretical study showed the possibility that boswellic acid could act as an anticancer agent via interaction with CDK2 (cell division protein kinase 2) using ArgusLab 4.0.1 software.[37] Besides, the DockingServer program was used to determine the interaction of some quinolone derivatives with RSK-4 (ribosomal S6 kinase 4); it is important to mention that these results suggest that quinolone derivatives could decrease cancer growth.[38] Analyzing all these data, in this study the interaction of twenty-seven bicyclo derivatives with VEGFR-1, VEGFR-2, and VEGFR-3 was determined using 3hng, 2oh4, and 4bsj proteins in the DockingServer program. Besides, it is important to mention that axinib, cediranib, cabozatinib, pazonib, regorafenib, and sorafinib drugs were used as controls. The results showed different aminoacid residues of interaction bicyclo derivatives (compounds 1-27) with 3hng protein surface compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs (Table 1).

 

 

Table 1. Interaction of bicyclic derivatives (1-27), axitinib, cabozantinib, pazopanib, and regorafenib with amino acid residues of 3hng protein surface.

Compound

Aminoacid residues

Axitinib

Val841; Glu878; Ile881; Leu882; Val891; Val892; Leu1013; Cys1018; His1020; Leu1029; Ile1038; Cys1039; Asp1040; Phe104

Cabozantinib

Val841;  Ala859;  Lys861;  Glu878;  Ile881;  Leu882;  Val892;  Val907;  Val909;  Cys1018; His1020; Leu1029; Ile1038; Cys1039; Asp1040; Phe1041

Pazopanib

Leu833;   Glu878;   Leu882;   Val892;   Val909;   Tyr911;   Cys912;   His1020;   Leu1029; Cys1039; Asp1040; Phe1041

Regorafenib

Val841;  Ala859;  Lys861;  Glu878;  Leu882;  Ile885;  Ile881;  Val892;  Val907;  Val909; Cys912; Leu1013; Cys1018; Ile1019; His1020; Leu1029; Asp1040; Phe1041

1

Val841; Lys861; Glu878; Ile881; Leu882; Ile885; Val892; Leu1013; Cys1018; His1020; Ile1038; Cys1039; Asp1040; Phe1041

2

Val841; Ala859; Lys861; Glu878; Leu882; Val891; Val892; Val909; Cys912; Leu1029; Cys1039; Phe1041

3

Glu878; Ile881; Leu882; Ile885; Val891; Leu1013; Cys1018; His1020; Ile1038; Asp1040

4

Val841; Lys861; Glu878; Leu882; Val892; Val909; Asp1040

5

Asp807; Thr877; Glu878; Ile881; Ile1019; Arg1021; Asp1040

6

Cys1018; His1020; Asp1040

7

Val841; Ala859; Lys861; Glu878; Val892; Val909; Leu1029; Cys1039; Phe1041

8

Val841; Ala859; Lys861; Glu878; Val892; Val909; Leu1029; Cys1039

9

Glu878; Ile881; Leu882; Ile885; Val891; Leu1013; Cys1018; His1020; Ile1038; Asp1040

10

Val841; Ala859; Lys861; Val909; Leu1029; Cys1039; Phe1041

11

Val841; Lys861; Glu878; Val909; Leu1029; Cys1039; Asp1040; Phe1041

12

Val841; Ala859; Lys861; Val909; Cys1039

13

Val841; Lys861; Val909; Cys1039; Phe1041

14

Asp807; Glu878; Ile881; Leu1013; Cys1018; His1020; Arg1021; Ile1038; Asp1040

15

Ala859; Lys861; Glu878; Ile881; Leu882; Ile885; Val891; Val892; Val909; Leu1013; Cys1018; Leu1029; Cys1039; Asp1040

16

Val841; Ala859; Lys861; Val892; Val909; Leu1029; Cys1039; Phe1041

17

Val841; Lys861; Glu878; Leu882; Val892; Val907; Val909; Leu1029; Cys1039; Phe1041

18

Val841; Lys861; Val909; Leu1029; Cys1039; Phe1041

19

Val841; Lys861; Glu878; Val892; Val909; Cys1039; Phe1041

20

Val841; Ala859; Lys861; Val892; Val909; Cys1039

21

Val841; Ala859; Lys861; Val892; Val909; Cys1039

22

Val841; Ala859; Lys861; Val892; Val909; Leu1029; Cys1039; Phe1041

23

Val841; Lys861; Glu878; Val909

24

Val841; Ala859; Lys861; Glu878; Val892; Val909

25

Val841; Ala859; Lys861; Glu878; Val892; Val909; Cys1039; Phe1041

26

Val841; Ala859; Lys861; Val909; Leu1029; Cys1039; Phe1041

27

Val841; Ala859; Lys861; Glu878; Leu882; Val892; Val909; Cys1039;

Other data indicate that the inhibition constant (Ki) was lower for compounds 1 and 15 compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs (Table 2). It is noteworthy that interaction for compound 1 could be through of hydrophobic bond with Leu882 and a polar bond with His102 with a 3hng protein surface. In addition, compound 15 could involve coupling via hydrogen bond with Glu878, and Asp1040 with 3hng protein surface.

 

Table 2. Various energies at which carbazole analogs (1-26), decernotinib, and facitinib bind to the 3pjc protein surface.

Compound

A

B

C

D

E

F

Axitinib

-9.60

91.30

-10.00

-0.07

-10.07

886.38

Cabozantinib

-7.70

2.28

-8.77

-0.18

-8.95

1000.65

Pazopanib

-8.76

380.77

-10.15

-0.11

-10.26

999.38

Regorafenib

-5.05

198.17

-6.84

-0.09

-6.93

1004.77

1

-8.18

1.01

-9.13

-0.09

-9.22

832.63

2

-8.86

322.19

-9.76

-0.05

-9.81

778.327

3

-5.43

103.85

-6.76

+0.13

-6.62

601.43

4

-5.29

132.14

-5.78

-0.11

-5.89

452.762

5

-5.29

131.89

-5.91

-0.09

-6.00

618.227

6

-4.41

588.45

-3.42

-1.29

-4.71

324.656

7

-5.39

111.96

-5.65

-0.04

-5.69

442.002

8

-6.25

26.34

-6.72

-0.07

-6.79

506.598

9

-6.66

13.13

-7.14

+0.05

-7.09

577.614

10

-5.45

101.04

-5.46

+0.00

-5.45

328.935

11

-6.51

16.89

-6.54

+0.03

-6.51

420.898

12

-5.27

138.19

-5.56

-0.00

-5.56

378.072

13

-4.73

339.02

4.73

-0.00

-4.73

353.959

14

-6.93

8.30

-7.66

-0.01

-7.67

757.683

15

-7.82

1.85

-9.93

-0.05

-9.98

896.067

16

-4.63

404.38

-5.14

-0.09

-5.23

405.007

17

-6.74

11.50

-6.81

-0.09

-6.90

57.287

18

-4.13

932.21

-4.14

+0.00

-4.13

328.053

19

-4.96

233.30

-5.21

-0.05

-5.25

369.284

20

-5.02

210.70

-5.03

+0.01

-5.02

361.576

21

-5.27

137.86

-5.34

+0.07

-5.27

397.849

22

-5.53

88.52

-5.55

+0.02

-5.53

411.912

23

-4.46

540.62

-4.45

-0.01

-4.46

330.74

24

-5.33

123.09

-5.35

+0.01

-5.33

354.272

25

-5.52

90.67

-5.45

-0.06

-5.52

406.755

26

-5.77

58.74

-5.76

-0.02

-5.77

423.77

27

-6.85

9.52

-6.85

+0.00

-6.85

459.872

A = Est: Free Energy of Binding (kcal/mol); B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

 

Other data suggest that coupling of bicyclo derivatives (compounds 1-27) with 2oh4 protein displayed differences in amino acid residues involved in 2oh4 protein surface compared with cabozantinib and cediranib drugs (Table 3).

 

Table 3. Coupling of bicyclic derivatives (1-27), cabozantinib, and cediranib with amino acid residues of 2oh4 protein surface.

Compound

Aminoacid residues

Cabozantinib

Arg840; Arg1049; Ile1051; Lys1053; Asp1054

Cediranib

Arg840; Lys869; Arg1049; Lys1053; Asp1054; Pro1055

1

Arg840; Lys869; Lys1053; Asp1054; Pro1055

2

Arg840; Ala842; Lys869; Arg1049; Lys1053; Asp1054

3

Arg840; Gly841; Ala842; Lys869; Asp1054

4

Arg1030; Arg1049; Asp1050; Ala1063; Pro1066

5

Pro837; Arg840; Arg1049; Lys1053

6

Asp1054; Pro1055; Asp1056

7

Arg1030; Ala1048; Asp1050; Ile1051; Arg1064; Pro1066

8

Arg840; Lys1053

9

Arg840; Lys869; Arg1049; Lys1053; Asp1054

10

Arg1030; Ala1048; Asp1050; Ile1051; Arg1064; Pro1066

11

Arg1030; Ala1048; Asp1050; Ile1051; Arg1064; Pro1066

12

Phe843; Lys866; Leu868; Ala879; Leu880; Glu883

13

Phe843; Lys866; Leu868; Glu876; Ala879; Leu880

14

Pro837; Arg840; Arg1030; Arg1049; Asp1050; Lys1053; Asp1062

15

Arg840; Ala842; Lys869; Arg1049; Lys1053

16

Lys869; Thr873; Glu876

17

Ala842; Lys869

18

Phe843; Lys866; Leu868; Ala879; Leu880

19

Arg1030; Ala1048; Asp1050; Ile1051; Arg1064; Pro1066

20

Arg1030; Asp1050; Ile1051; Pro1066

21

Arg1030; Ala1048; Asp1050; Ile1051; Arg1064; Pro1066

22

Arg840; Lys869

23

Phe843; Lys866; Leu868; Glu876; Ala879; Leu880

24

Phe843; Lys866; Leu868; Glu876; Ala879; Leu880; Glu883

25

Arg1030; Asp1050; Arg1064; Pro1066

26

Asp1026; Arg1030; Asp1050; Ile1051; Arg1064; Pro1066

27

Arg1030; Ala1048; Asp1050; Ile1051; Pro1066

 

Furthermore, the Ki was lower for bicyclo derivatives 4, 7, 8, 10, 12, and 15-22 compared with cabozatinib and cediranib drugs (Table 4). This phenomenon, could due to interaction of compounds 4, 7, 8, 10, 12, and 15-22 with some aminoacid residues; for example for compound 4 through hydrogen bond with Arg1049 and hydrophobic bond with Pro1066; for 7 via hydrophobic bond with Ala1048, Ile1051, and Pro1066; for with Arg840, and Lys1053; for compound 10 through hydrogen bond with Arg1064 and hydrophobic bond with Ala1048 and Ile1051; for 12 via hydrophobic bond with Phe843, Leu868, Ala879 and Leu880; for compound 15 through hydrogen bond with Arg840 and hydrophobic bond with Ala842; for 16 via polar bound with Glu876; for 17 with aminoacid residues such as Ala842 and Lys869; for 18 through hydrophobic bond with Phe843, Leu868, Ala879 and Leu880; for 19 via polar bond Arg1030 and Arg1064 and hydrophobic bond with Ala1048, Ile1051 and Pro1060; for compound 20 through polar bound with Arg1030 and hydrophobic bond with Ile1051 and Pro1066; for 21 via polar bound with Arg1030 and  Arg1064 and hydrophobic bond with Ala1048, Ile1051 and Pro1066; for compound 22 with Arg840 and Lys869.

 

Table 4. Thermodynamics parameters involved in the interaction of bicyclic derivatives (1-27), cabozantinib, and cediranib with 2oh4 protein surface.

Compound

A

B

C

D

E

F

Cabozantinib

-5.15

168.22

-5.81

-0.18

-5.99

671.90

Cediranib

-4.53

474.23

-4.75

-0.39

-5.14

615.74

1

-4.32

686.33

-5.31

-0.14

-5.44

593.403

2

-4.66

380.73

-5.55

+0.00

-5.55

625.531

3

-4.21

825.61

-5.30

-0.10

-5.40

509.798

4

-3.72

1.88

-4.15

-0.17

-4.32

486.822

5

-4.83

289.72

-5.21

-0.01

-5.23

512.918

6

-4.32

684.73

-2.17

-2.44

-4.62

185.871

7

-3.69

1.96

-3.78

-0.21

-3.99

437.277

8

-3.68

1.99

-4.22

-0.06

-4.27

453.462

9

-4.62

412.93

-5.29

+0.07

-5.22

517.217

10

-4.00

1.17

-3.95

-0.05

-4.00

307.113

11

-4.50

501.37

-4.44

-0.06

-4.50

392.868

12

-3.85

1.52

-4.14

-0.00

-4.14

346.732

13

-4.13

939.89

-4.13

-0.00

-4.13

311.138

14

-6.64

13.48

-7.31

-0.05

-7.36

662.596

15

-3.94

1.29

-6.15

+0.06

-6.08

678.07

16

-3.37

3.37

-3.64

-0.33

-3.97

309.652

17

-3.80

1.64

-3.67

-0.06

-3.73

398.224

18

-3.65

2.10

-3.65

-0.00

-3.65

285.446

19

-3.65

2.11

-3.84

-0.11

-3.95

338.907

20

-3.90

1.39

-3.79

-0.11

-3.90

334.548

21

-4.05

1.08

-3.87

-0.17

-4.05

370.26

22

-3.56

2.44

-3.70

+0.13

-3.56

351.532

23

-4.16

887.31

-4.13

-0.03

-4.16

307.633

24

-4.31

696.25

-4.32

+0.01

-4.31

322.443

25

-4.15

910.75

-3.98

-0.17

-4.15

388.441

26

-3.96

1.26

-4.04

+0.09

-3.96

413.098

27

-4.43

570.49

-4.31

-0.11

-4.43

443.151

A = Est: Free Energy of Binding (kcal/mol); B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

 

Finally, other data (Table 5) indicate that there are differences in the number of amino acid residues involved in the interaction of bicyclo derivatives 1-27 with 4sbj protein surface compared with axitinib, and cediranib drugs.

 

 

Table 5. Coupling of bicyclic derivatives (1-27), axitinib, and cediranib with amino acid residues of 4sbj protein surface.

Compound

Aminoacid residues

Axitinib

Ala400; Leu401; Trp402; Arg409; Arg410; Asn411

Cediranib

Tyr369; Ala400; Trp402; Arg409; Asn411

1

Tyr369; Thr398; Ala400; Trp402; Ser404; Arg409; Asn411

2

Tyr369; Thr398; Ala400;, Arg409; Asn411

3

Tyr369; Ala400; Trp402; Arg409; Asn411

4

Ala400; Trp402; Arg409; Asn411

5

Tyr369; Ala400; Leu401; Trp402; Arg409; Asn411

6

Ala400; Leu401; Trp402; Arg409; Arg410; Asn411

7

Ala400; Trp402; Arg409; Asn411

8

Ala400; Trp402; Arg409; Asn411

9

Tyr369; Ala400; Trp402; Arg409; Asn411

10

Tyr369; Ala400; Trp402; Arg409; Asn411

11

Tyr369; Ala400; Trp402; Arg409; Asn411

12

Ala400; Trp402; Arg409; Asn411

13

Ala400; Trp402; Arg409; Asn411

14

Tyr369; Thr398; Ala400; Trp402; Asn411

15

Tyr369; Thr398; Ala400; Trp402; Arg409; Asn411

16

Ala400; Trp402; Arg409; Asn411

17

Tyr369; Ala400; Trp402; Arg409; Asn411

18

Ala400; Trp402; Arg409; Asn411

19

Ala400; Trp402; Arg409; Asn411

20

Ala400; Trp402; Arg409; Asn411

21

Ala400; Trp402; Arg409; Asn411

22

Ala400; Trp402; Arg409; Asn411

23

Ala400; Trp402; Arg409; Asn411

24

Ala400; Trp402; Arg409; Asn411

25

Ala400; Trp402; Arg409; Asn411

26

Ala400; Trp402; Arg409; Asn411

27

Trp402; Arg409; Asn411

 

Besides, the Ki for bicyclo derivatives of compounds 4, 6-8, 10, 12, 13, 16, 18-21, 23, 24, and 26 was lower compared with axitinib and cediranib drugs. This results could be to coupling of different aminoacid residues involved in each protein surface; for example for bicyclo derivative 4  (Table 6) through polar bound with Arg4090 and Asn411; hydrophobic bond with Ala400 and Trp402; for 6 via hydrogen bond Leu401, Arg410 and Asn411 and hydrophobic bond with Ala400 and Trp402; for 7  through polar bond Arg409 and hydrophobic bond with Ala400 and Trp402; for 8 via hydrophobic bond with Ala400 and Trp402; for compound 10 through hydrophobic bound with Ala400 and Trp402 and halogen-bond Tyr369; for 12 via hydrophobic bond with Ala400 and Trp402; for 13 through hydrophobic bond with Ala400 and Trp402; for 16 via polar bond Arg409 and Asn411 and hydrophobic bond with Ala400 and Trp402; for compound 18 through hydrophobic bond with Ala400 and Trp402; for 19 via polar bound with Asn411 and hydrophobic bond with Ala400 and Trp402; for 20 through hydrophobic bond with Ala400 and Trp402; for 21 via polar bound with Arg409 and hydrophobic bond with Ala400 and Trp402; for 23 through hydrophobic bond with Ala400 and pi-pi bound with Trp402; for 24 via hydrophobic bond with Ala400 and Trp402; for 26 through hydrophobic bond with Ala400 and Trp402.

 

Table 6. Thermodynamics parameters involved in the interaction of bicyclic derivatives (1-27), axitinib, and cediranib with 4bsj protein surface.

Compound

A

B

C

D

E

F

Axitinib

-6.96

7.87

-7.74

0.00

-7.74

629.46

Cediranib

-4.92

248.37

-4.71

0.11

-4.60

475.52

1

-4.83

288.81

-6.05

+0.02

-6.03

642.309

2

-4.75

327.53

-5.53

-0.01

-5.54

571.586

3

-4.26

756.37

-5.41

-0.04

-5.45

468.482

4

-3.27

4.04

-3.77

-0.09

-3.86

364.033

5

-4.70

358.24

-5.47

-0.00

-5.47

461.545

6

-3.32

3.71

-3.52

-0.10

-3.61

265.362

7

-3.93

1.32

-4.04

-0.18

-4.22

361.663

8

-3.87

1.47

-4.43

+0.03

-4.41

407.43

9

-4.65

392.57

-4.94

-0.07

-5.02

429.595

10

-3.97

1.24

-3.95

-0.02

-3.97

266.541

11

-4.48

520.45

-4.46

-0.01

-4.48

345.514

12

-3.92

1.35

-4.21

-0.00

-4.21

311.676

13

-3.87

1.46

-3.87

-0.00

-3.87

289.115

14

-4.44

555.92

-5.15

-0.00

-5.15

545.316

15

-4.21

826.34

-6.10

+0.02

-6.08

659.82

16

-3.23

4.30

-3.79

-0.04

-3.83

324.767

17

-4.73

343.36

-4.66

-0.02

-4.68

381.591

18

-3.56

2.44

-3.56

-0.01

-3.56

263.194

19

-3.84

1.53

-4.11

-0.03

-4.14

299.916

20

-3.99

1.18

-4.00

+0.00

-3.99

289.691

21

-4.02

1.14

-3.95

-0.07

-4.02

328.993

22

-4.25

766.59

-4.17

-0.08

-4.25

345.759

23

-3.50

2.71

-3.51

+0.01

-3.50

278.369

24

-4.05

1.08

-4.04

-0.01

-4.05

292.545

25

-4.18

863.98

-4.11

-0.07

-4.18

338.722

26

-4.04

1.10

-3.97

-0.07

-4.04

333.875

27

-4.45

545.67

-4.43

-0.02

-4.45

365.436

A = Est: Free Energy of Binding (kcal/mol); B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

Conclusion

This research has reported the interaction of bicyclo analogs to the VEGR-1, VEGR-2, AND VEGR-3 surface using 3hng, 2oh4, and 4bsj proteins as theoretical tools. The results indicated the following; i) bicyclo derivatives 1 and 15 could have a higher affinity for 3hng protein surface compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs; ii) Besides, the Ki for coupling of 4, 7, 8, 10, 12, and 15-22 with 2oh4 protein surface was lower compared with cabozatinib and cediranib drugs. Finally, the results for the interaction of bicyclo analogs 4, 6-8, 10, 12, 13, 16, 18-21, 23, 24, and 26 were lower compared with axitinib and cediranib drugs. All these data suggest that bicyclo derivatives 1, 4, 6-8, 10, 12, 13, 15-24, and 26 could modulate the biological activity produced by VEGR-1, VEGR-2, and VEGR-3; this phenomenon could translated as good anticancer agents.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

None.

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Cite this article
Vancouver
Lopez-Ramos M, Figueroa-Valverde L, Rosas-Nexticapa M, Alvarez-Ramirez M, Mateu-Armand V, Cauich-Carrillo R. Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer. Clin Cancer Investig J. 2024;13(5):1-9. https://doi.org/10.51847/tFgoN65qlJ
APA
Lopez-Ramos, M., Figueroa-Valverde, L., Rosas-Nexticapa, M., Alvarez-Ramirez, M., Mateu-Armand, V., & Cauich-Carrillo, R. (2024). Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer. Clinical Cancer Investigation Journal, 13(5), 1-9. https://doi.org/10.51847/tFgoN65qlJ

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