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


Publisher: Deniz Publication
ARTICLE
Year: 2023   |   Volume: 12   |   Issue: 3   |   Page: 13-18     View issue

Analysis of Interaction between Twenty-Seven Pyrimidinone Derivatives with XIAP Using a Theoretical Model

Lauro Figueroa-Valverde1*, Francisco Diaz-Cedillo2, Marcela Rosas-Nexticapa3, Catalina Cervantes-Ortega3, Magdalena Alvarez-Ramirez3, Virginia Mateu-Armand3, Maria Lopez-Ramos1

1Departament of Chemistry, Laboratory of Pharmacochemistry Research, Faculty of Biological-Chemical Sciences, University Autonomous of Campeche; Humberto Lanz Cárdenas s/n, Ex Hacienda Kalá, C.P. 24085, Campeche, Mexico. 2Departament of Organic Chemistry, Biological Sciences, National Politechnic Institute; Prolongacion de Carpio y Plan de Ayala s/n, Col. Sto Tomas, 11340, Mexico. 3Departament of Nutrition, Faculty of Nutrition, University of Veracruz, Medicos y s/n Odontologos 910210, Unidad del Bosque, Xalapa, Mexico.


Abstract

For several years, several drugs have been used to treat different types of cancer; however, some of these drugs can cause side effects, such as high blood pressure, liver damage, and erectile dysfunction. In the search for new therapeutic alternatives, some compounds have been developed for the treatment of this clinical pathology; however, the interaction of these drugs with some biomolecules involved in the development of cancer is very unclear. Analyzing this data, this investigation aimed to evaluate the possible theoretical interaction of some pyrimidinone derivatives (compounds 1 to 27) on the X-linked inhibitor of apoptosis protein (XIAP) involved in cancer using the Docking model. The results showed that some pyrimidinone derivatives (1-6, 10, 11, 14, 15, 22-24, 26, and 27) could interact with the XIAP protein surface. In conclusion, these data suggest that some pyrimidinone derivatives can produce changes in the biological activity of XIAP. Therefore, these pyrimidinone derivatives could be good candidates to treat cancer.

Keywords: Cancer, Pyrimidinone derivatives, XIAP, Docking


Introduction

Several data indicate that cancer is one of the main causes of death worldwide, which translates into a decreased life expectancy of the population.[1-9] This clinical pathology has been increasing in both developed and developing countries due to various factors involved such as aging and population growth.[10-13] In addition, some biomolecular signaling systems are activated to produce cancer; for example, there are some studies indicating that X-linked inhibitors of apoptosis protein (XIAP) may regulate cell death signaling pathways through the binding and inhibition of caspases.[14-16] In addition, other data suggest that XIAP may be involved in the development of several types of cancer.[17-23] In this way, some drugs have been developed; for example, a study showed that Clioquinol (5-chloro-7-iodo-8-quinolinol) induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP) translated as a decrease of prostate cancer.[24] Other data showed that compound (3S,6S,9R,10aR)-6-((S)-2-(Methylamino)propanamido)-5-oxo 9-(2-phenylacetami-do)-N-((R)-1,2,3,4-te-trahydronaphthalen-1-yl)decahydropyrrolo [1,2-a]azocine-3-carboxamide decreases the growth of cancer cells (MDA-MB-231) through XIAP inhibition.[25] Besides, a report displayed the synthesis of a series of benzodiazepinones as XIAP selective inhibitors for the treatment of cancer using an in vitro model.[26] In addition, a study carried out on human gastric cancer cell lines AGS (adenocarcinoma), KATO-III (signet-ring cell carcinoma), and NCI-N87 (gastric carcinoma) showed that Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquino-ne) can decrease the expression of XIAP translated as cell cycle arrest at the S and G2/M phases and apoptosis.[27] Furthermore, a study showed that embelin acts as an inhibitor of XIAP using human prostate cancer cell lines (PC-3, LNCap, CL-1, DU-145).[27] Other data show that some diazabicyclic derivatives inhibit the expression of XIAP using some cancer cell lines such as MDA-MB-231 and SK-OV-3.[28] All these data suggest that some drugs can decrease the expression of XIAP, which translates as changes in the growth of some cancer cells; however, there is little information in the literature on the interaction of pyrimidinone with XIAP protein.

 

Perhaps this is due to the diverse experimental designs that focus on multiple

 

molecular mechanisms involved in cancer. Analyzing this hypothesis, the objective of this study was to evaluate the interaction of twenty-seven pyrimidinone derivatives with XIAP using a theoretical model.

Materials and Methods

Twenty-seven pyrimidinone derivatives previously reported in PubChem.[29] (Figure 1) were used to evaluate the possible interaction with X-linked inhibitor of apoptosis protein (XIAP) as follows:

Figure 1. Chemical structure of XIAP inhibitors (A, B, and C) and pyrimidinone derivatives (1-27)

A = (3S,6S,9R,10AR)-6-((S)-2-(Methylamino)propanamido)-5-oxo-9-(2-phenylacetami- do)-N-((R)-1,2,3,4-tetrahydronaphthalen-1-yl)decahydropyrrolo[1,2-a]azo-cine-3-car-boxamide.[25]

B = N-(3,4-Dimethylphenyl)-4-(4-isobutyrylphenyl)-2,3,3a,4,5,9bhexahydrofuro [3,2-c]quinoline-8-sulfonamide.[30]

C = (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-((4-cyanophenyl)(methyl)amino)-2-hydroxy-2-methylpropanamide).[31]

1 = 1,3-Dimethyl-3,4,5,6,-tetrahydro-2(1H)-pyrimidinone

2 = 1-isopropyltetrahydro-2(1H)-pyrimidinone

3 = 2-(1,4-Diazepan-1-yl)-6-(methoxymethyl)-4(3H)-pyrimidinone

4 = 2-(1,4-Diazepan-1-yl)-6-ethyl-4(3H)-pyrimidinone

5 = 2-(1,4-Diazepan-1-yl)-6-methyl-4(3H)-pyrimidinone

6 = 2-(1,4-Diazepan-1-yl)-6-propyl-4(3H)-pyrimidinone

7= 2-(Benzylamino)-4(3H)-Pyrimidinone

8= 2-(Methylsulfanyl)-6-propyl-4(3H)-pyrimidinone

9= 2-Amino-6-(4-fluorophenyl)-4(3H)-pyrimidinone

10= 2-ethoxy-4(3H)-pyrimidinone

11= 4,6-Dimethyl-2(1H)-Pyrimidinone

12= 4-Amino-1-benzyl-2(1H)-pyrimidinone

13= 4-Amino-1-[(3,5-dimethyl-4-isoxazolyl)methyl]-2(1H)-pyrimidinone

14= 5-Fluoro-2-ethoxy-4(1H)pyrimidinone

15= 5-Fluoro-6-methoxy-2(1H)-pyrimidinone

16= 6-(3-Bromophenyl)-1-methyl-5-(3-methyl-5-isoxazolyl)-2(1H)-pyrimidinone

17= 6-(Chloromethyl)-2-(2-pyrazinyl)-4(3H)-pyrimidinone

18= 6-(Chloromethyl)-2-(3,4-difluorophenyl)-4(3H)-pyrimidinone

19= 6-(Chloromethyl)-2-(3-chlorophenyl)-4(3H)-pyrimidinone

20= 6-(Chloromethyl)-2-(4-ethylphenyl)-4(3H)-pyrimidinone

21= 6-(Chloromethyl)-2-(4-methoxyphenyl)-4(3H)-pyrimidinone

22= 6-(Dimethylamino)-5-fluoro-2(1H)-pyrimidinone

23= 6-(Methoxymethyl)-2-(1-piperazinyl)-4(3H)-pyrimidinone

24= 6-Amino-2-(methylsulfanyl)-4(3H)-pyrimidinone

25= 6-Butyl-2-(1-piperazinyl)-4(3H)-pyrimidinone

26= 6-Ethyl-2-(1-piperazinyl)-4(3H)-pyrimidinone

27= 6-Ethyl-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone

 

Ligand-protein evaluation

The interaction of twenty-seven pyrimidinone derivatives with XIAP was evaluated using 4ic2[32] protein as a theoretical model using some XIAO inhibitors (compounds A, B, and C)[25, 30, 31] as control. In addition, binding energy involved in the interaction of pyrimidinone derivatives with the 4ic2 protein surface was evaluated using DockingServer software.[33]

 

Pharmacokinetics parameter

Pharmacokinetic parameters were determined using the SwissADME software.[34]

 

Toxicity evaluation

The possible toxicity produced by pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was determined using the GUSAR software.[35]

 

Results and Discussion

The literature reports are indicating that some compounds can produce changes in the biological activity of XIAP,[24-27] resulting in a decrease in the growth of cancer cells. However, there are data on the interaction of pyrimidinone derivatives with XIAP, which translates into insufficient information on the effect that these compounds could produce on cancer cells.

Protein-ligand analysis

This study aimed to evaluate the interaction of twenty-seven pyrimidinone derivatives with XIAP using 4ic2 protein and compounds A, B, and C (Figure 1) as theoretical tools in a Docking model.[33] The results showed in Table 1 and Figure that different amino acid residues are involved in the interaction of pyrimidinone derivatives with XIAP; this data suggest that this interaction is due to different functional groups involved in the chemical structure of each pyrimidinone derivative (Table 1, Figures 2 and 3).

Table 1. Aminoacid residues are involved in the interaction of pyrimidinone derivates with the 4ic2-protein surface

Compound

Aminoacid residues

A

Glu447; Lys448; Lys451; Asn457; Ile458; Leu468; Met483; Ile494; Met496

B

Leu444; Glu447; Lys448; Lys451; Ile458; Leu468; Met496

C

Lys448; Ile458; Leu468; Met483; Ile494; Phe495; Met496

1

Lys448; Asn457; Ile458; Leu468; Ile494; Met496

2

Lys448; Asn457; Ile458; Ile494; Met496

3

Leu444; Glu447; Lys448; Ile458; Leu468; Met496

4

Leu444; Glu447; Lys448; Ile458; Leu468; Met496

5

Glu447; Lys448; Ile458; Leu468; Met496

6

Leu444; Glu447; Lys448; Ile458; Met496

7

Lys448; Ile458; Ala459; Leu468; Ile494; Phe495; Met496

8

Lys448; Ile458; Leu468; Ile494; Met496

9

Leu444; Glu447; Lys448; Ile458; Ile494; Met496

10

Lys448; Ile458; Ala459; Ile494; Met496

11

Ile458; Ala459; Ile494; Phe495; Met496

12

Lys448; Asn457;Ile458; Ala459; Ile494; Phe495; Met496

13

Glu447; Ile458; Gly466; His467; Leu468

14

Lys448; Ile458; Ile494; Met496

15

Lys448; Ile458; Ala459; Ile494; Met496

16

Leu444; Glu447; Lys448; Ile458; Leu468; Met496

17

Glu447; Lys448; Ile458; Leu468; Ile494; Met496

18

Lys448; Asn457; Ile458; Leu468; Ile494; Phe495; Met496

19

Asn457; Ile458; Ala459; Ile494; Phe495; Met496

20

Glu447; Lys448; Ile458; Leu468; Ile494; Met496

21

Glu447; Lys448; Ile458; Ala459; Leu468; Ile494; Met496

22

Lys448; Asn457; Ile458; Ala459; Ile494; Met496

23

Glu447; Lys448; Ile458; Leu468

24

Lys448; Asn457; Ile458; Leu468; Ile494; Met496

25

Leu444; Glu447; Lys448; Ile458; Leu468

26

Leu444; Glu447; Lys448; Ile458; Leu468; Met496

27

Glu447; Lys448; Ile458

 

 

Figure 2. The scheme showed different amino acid residues involved in the interaction of some pyrimidinone derivatives (1-6, 10, and 11) with a 4ic2-protein surface using DockingServer software.[30]

 

Figure 3. Interaction of pyrimidinone derivatives (14, 15, 22, 23, 24, 26, and 27) with the 4ic2-protein surface involves several amino acid residues involved. Scheme visualized with the DockingServer software.[30]

Binding energies

Some studies indicate that the ligand-protein interaction may depend on the energy levels such as the binding free energy, Electrostatic energy, total intermolecular energy, and Van der Waals forces.[34] Analyzing these data, in this study, several thermodynamic factors involved in the interaction of pyrimidinone-derivatives with 4ic2 protein surface were evaluated using some XIAO-inhibitors such as compounds A, B, and C as controls. The results showed differences in the energy levels involved in the interaction of pyrimidinone derivatives with the 4ic2 protein surface compared with the controls (Table 2). Other results show that inhibition constant (Ki) pyrimidinone-derivatives (2, 3, 4, 6, 22, 24, and 26) was lower, compared with the controls (A, B, and C). In addition, the Ki for pyrimidinone-derivatives 1, 5, 10, 11, 14, 15, 23, and 27 were lower compared with the controls A and C. This phenomenon suggests that pyrimidinone derivatives such as 1-6, 10, 11, 14, 15, 22-22-24, 25, and 27 could inhibit the biological activity of XIAO protein translated as a possible decrease in prostate cancer levels.

 

Table 2. Thermodynamic parameters involved in the interaction of pyrimidinone derivates with the 4ic2-protein surface.

Compound

I

II

II

IV

V

VI

A

-6.88

9.04

-8.41

-0.14

-8.55

860.34

B

-7.79

1.94

-6.75

-0.73

-7.48

725.16

C

-5.60

78.24

-7.53

+0.05

-7.48

745.32

1

-3.15

4.92

-3.09

-0.06

-3.15

380.46

2

-3.94

1.30

-4.15

-0.09

-4.24

440.55

3

-3.89

1.40

-3.71

-0.93

-4.64

490.22

4

-3.92

1.35

-3.60

-1.00

-4.60

489.58

5

-3.64

2.13

-3.05

-0.89

-3.94

462.71

6

-3.88

1.43

-3.84

-0.92

-4.75

519.73

7

-5.20

153.39

-5.73

-0.06

-5.79

545.63

8

-4.17

873.21

-5.06

-0.02

-5.08

489.01

9

-4.98

222.21

-5.13

-0.15

-5.28

495.88

10

-3.33

3.65

-3.81

-0.10

-3.91

437.03

11

-3.51

2.68

-3.45

-0.06

-3.51

350.85

12

-4.97

227.23

-5.75

-0.12

-5.87

526.51

13

-4.16

886.57

-4.99

-0.05

-5.04

462.63

14

-3.52

2.62

-4.12

+0.01

-4.11

430.46

15

-3.68

2.01

-3.87

-0.10

-3.98

389.157

16

-5.40

109.27

-5.69

-0.18

-5.87

596.089

17

-4.47

533.28

-4.86

-0.35

-5.22

536.748

18

-5.46

100.33

-5.87

-0.34

-6.21

546.824

19

-5.22

148.08

-5.95

-0.06

-6.00

596.423

20

-5.32

126.81

-6.14

-0.22

-6.36

610.769

21

-4.58

436.01

-5.80

+0.04

-5.76

615.318

22

-3.76

1.74

-3.91

-0.15

-4.06

432.66

23

-3.65

2.10

-3.53

-1.01

-4.53

513.375

24

-3.79

1.66

-4.35

-0.04

-4.39

436.637

25

-4.49

507.65

-4.52

-1.03

-5.55

551.579

26

-4.00

1.17

-3.62

-0.99

-4.61

488.779

27

-3.66

2.09

-3.87

-0.09

-3.96

419.721

I = Free Energy of Binding (kcal/mol)

II = Inhibition Constant, Ki (mM)

III = Vander Waals forces + H-bond + desolv Energy (kcal/mol)

IV = Electrostatic Energy (kcal/mol)

V = Total Intermolecular Energy (kcal/mol)

VI = Interaction Surface

Pharmacokinetic analysis

In the literature, there are methods to predict some pharmacokinetic parameters for different drugs, such as PK/PD,[36] MONOLIX,[37] CXTMAIN,[38] and SwissADME.[39] In this research, some pharmacokinetic factors involved in pyrimidinone derivatives were evaluated using SwissADME software (Table 3). The results showed differences in gastrointestinal absorption and metabolism (involving different types of cytochrome P450 systems) of pyrimidinone derivatives compared with the controls. This data suggest that the pharmacokinetics of pyrimidinone derivatives could depend on their chemical structure.

Table 3. Pharmacokinetic parameters for pyrimidinone derivatives

Compound

i

ii

iii

iv

v

vi

vii

viii

ix

A

High

No

Yes

No

Yes

No

Yes

Yes

4.59

B

High

No

Yes

No

Yes

No

Yes

Yes

2.92

C

High

No

Yes

No

No

No

No

Yes

2.68

1

Low

No

No

No

No

No

No

No

0.33

2

High

No

No

No

No

No

No

No

0.73

3

High

No

Yes

No

No

No

No

No

0.11

4

High

No

Yes

No

No

No

No

No

0.72

5

High

No

Yes

No

No

No

No

No

0.43

6

High

No

Yes

No

No

No

No

No

1.04

10

High

No

No

No

No

No

No

No

0.65

11

High

No

No

No

No

No

No

No

0.73

14

High

Yes

No

No

No

No

No

No

0.95

15

High

No

No

No

No

No

No

No

0.56

22

High

No

No

No

No

No

No

No

0.61

23

High

No

Yes

No

No

No

No

No

0.11

24

High

No

No

No

No

No

No

No

0.23

26

High

No

Yes

No

No

No

No

No

0.72

27

High

No

No

No

No

No

No

No

1.24

i = GI absorption

ii = BBB permeant

iii = P-GP substrate

iv = CYP1A2 inhibitor

v = CYP2C19 inhibitor

vi = CYP2C9 inhibitor

vii = CYP2D6 inhibitor

viii = CYP3A4 inhibitor

ix = Consensus Log PO/W

                     

Toxicity analysis

Some data in the literature indicate that several pyrimidinone derivatives can produce toxicity in different biological models.[40-43] Analyzing these data, the possible toxicity produced by some pyrimidinone derivatives (2, 5, 9, 11, 13, and 15) was evaluated using the GUSAR software.[35] The results showed that compounds A, B, and C require higher doses to produce toxicity (LD50) through the intraperitoneal route compared to pyrimidinone derivatives; however, pyrimidinone derivatives could produce different toxicity degrees through intravenous, oral, and subcutaneous routes compared with the controls. These data suggest that the toxicity could depend on the dose and routes of administration of each pyrimidinone derivative.

Table 4. Theorethical toxicity produced by compouns A,B,C, and pyrimidinone derivatives (1-6, 10, 11, 14, 15 22-24 26 and 27) using the Gussar software.

Compound

IP LD50 (mg/kg)

IV LD50 (mg/kg)

Oral LD50 (mg/kg)

SC LD50 (mg/kg)

A

959.00

58.74

1265.00

79.10

B

689.10

46.93

1943.00

396.00

C

757.70

82.31

974.40

695.40

1

126.40

33.69

797.20

169.20

2

137.70

89.46

871.30

151.60

3

94.22

128.40

1196.00

611.90

4

93.290

104.30

1854.00

563.60

5

55.75

125.40

1925.00

159.10

6

78.37

64.300

1071.00

583.40

10

346.40

139.80

3856.00

463.20

11

218.10

105.30

3451.00

287.80

14

369.60

226.20

804.20

466.10

15

465.00

307.30

591.20

377.80

22

194.20

169.20

651.40

277.40

23

94.22

128.40

1196.00

611.90

24

298.70

255.50

658.80

604.90

26

93.29

104.30

1854.00

563.60

27

232.80

103.90

944.50

496.20

IP = Intraperitoneal.

IV = Intravenous.

Oral = Oral.

 SC = Subcutaneous.

Conclusion

Theoretical analyzes on the interaction of pyrimidinone derivatives with the 4ic2 protein surface suggest that pyrimidinone derivatives 1-6, 10, 11, 14, 15, 22-24, 26, and 27 might have a higher affinity for XIAP translated as greater XIAP inhibition compared with the controls. These data suggest that pyrimidinone derivatives could be good candidates to treat cancer through XIAP inhibition.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

This study developed out following the rules of professional ethics involved in the pharmacochemical research laboratory of the Autonomous University of Campeche.

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