J Food Bioact

Journal of Food Bioactives, ISSN 2637-8752 print, 2637-8779 online

Journal website www.isnff-jfb.com

Original Research

Volume 25, March 2024, pages 81-94

In silico ADME and molecular simulation studies of pharmacological activities of phytoconstituents of Annona muricata (L.) Fruit

Figure 3. Average rank of kinases and transcription factors across all the library.

Figure 4. Interaction of the binding poses of PDCD4 with: (a) Annonaine; (b) Asimilobine; (c) Dicaffeoylquinic acid; (d) Dihydrokaempferol-hexoside; (e) fisetin; (f) Kaempferol; (g) Kaempferol-3-O-rutinoside; (h) Luteolin-3,7-di-O-glucoside; (i) Morin; (j) Myricetin; (k) Nornuciferine; (l) Dexamethasone.

Figure 5. Protein-ligand complex simulation results (a) RMSD of Annonaine and PDCD4 (b) RMSF of PDCD4 on binding to Orientin. (c) Interaction profile of the contact between Annonaine and PDCD4 (d) RMSD of Dexamethasone and PDCD4. (e) RMSF of PDCD4 on binding to Quercetin; (f) Interaction profile of the contact between Dexamethasone and PDCD4.

Figure 6. A schematic of detailed ligand-protein interactions (a) Annonaine and PDCD4 (b) Dexamethasone and PDCD4.

**Table 1.** Predicted pharmacokinetics properties of selected ligands
SN	Ligands	Predicted ADME Parameter from SWISSADME
Physicochemical properties: Molecular weight (MW), Molar Refractivity (MR), Total polar surface area (TPSA). Lipophilicity: Consensus Log P. Water Solubility: ESOL Log S, ESOL Class. Pharmacokinetics: Gastrointestinal absorption (GIA), Blood-brain barrier (BBB), P-glycoprotein (P-gp) substrate, Inhibition of Cytochrome P450 (CYPs) type CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. Druglikeness: Lipinski (Lip), Bioavailability Score (BS), Medicinal Chemistry: Synthetic accessibility (SA).
1	Annonacin	596.88	172.67	116.45	6.92	−7.13	Poorly soluble	Low	No	No	CYP3A4	1	0.55	7.36
2	Annonacin-10-one	594.86	171.71	113.29	6.83	−6.8	Poorly soluble	Low	No	Yes	CYP3A4	1	0.55	7.18
3	Annonaine	265.31	80.13	30.49	2.88	−3.71	Soluble	High	Yes	Yes	CYP1A2, CYP2D6, CYP3A4	0	0.55	3.36
4	Cis-Annoreticuin	596.88	172.67	116.45	6.94	−7.13	Poorly soluble	Low	No	No	CYP3A4	1	0.55	7.36
5	Asimilobine	267.32	82.59	41.49	2.65	−3.54	Soluble	High	Yes	Yes	CYP1A2, CYP2D6, CYP3A4	0	0.55	3.24
6	Cinnamic acid	148.16	43.11	37.3	1.79	−2.37	Soluble	High	Yes	No	NONE	0	0.85	1.67
7	Corossolone	578.86	170.55	93.06	7.75	−7.66	Poorly soluble	Low	No	Yes	NONE	2	0.17	6.9
8	Coumaric acid	164.16	45.13	57.53	1.26	−2.02	Soluble	High	Yes	No	NONE	0	0.85	1.61
9	Dicaffeoylquinic acid	516.45	126.9	211.28	0.91	−3.65	Soluble	Low	No	Yes	NONE	3	0.11	4.83
10	Dihydrokaempferol-hexoside	450.39	105.12	186.37	−0.5	−2.8	Soluble	Low	No	Yes	NONE	2	0.17	5.24
11	Epoxymurin-A	530.86	167.55	38.83	10.35	−10.03	Insoluble	Low	No	Yes	NONE	2	0.17	6.47
12	Epoxymurin-B	530.86	167.55	38.83	10.37	−10.03	Insoluble	Low	No	Yes	NONE	2	0.17	6.47
13	Epomusenin-A	558.92	177.17	38.83	11.09	−10.75	Insoluble	Low	No	Yes	NONE	2	0.17	6.73
14	Epomusenin-B	558.92	177.17	38.83	11.08	−10.75	Insoluble	Low	No	Yes	NONE	2	0.17	6.73
15	Fisetin	286.24	76.01	111.13	1.55	−3.35	Soluble	High	No	No	CYP1A2, CYP2D6, CYP3A4	0	0.55	3.16
16	Kaempferol	286.24	76.01	111.13	1.58	−3.31	Soluble	High	No	No	CYP1A2, CYP2D6, CYP3A4	0	0.55	3.14
17	Kaempferol 3-O-rutinoside	594.52	139.36	249.2	−0.73	−3.42	Soluble	Low	No	Yes	NONE	3	0.17	6.48
18	Luteolin 3,7-di-O-glucoside	610.52	140.26	269.43	−1.49	−3.22	Soluble	Low	No	Yes	NONE	3	0.17	6.39
19	Montecristin	574.92	180.05	66.76	9.92	−9.64	Poorly soluble	Low	No	Yes	NONE	2	0.17	6.82
20	Morin	302.24	78.03	131.36	1.2	−3.16	Soluble	High	No	No	CYP1A2, CYP2D6, CYP3A4	0	0.55	3.25
21	Muricatetrocin B	470.64	129.41	116.45	3.8	−4.1	Moderately soluble	High	No	No	CYP3A4	0	0.55	6.21
22	Muricatocin A	612.88	173.84	136.68	6.17	−6.61	Poorly soluble	Low	No	No	CYP3A4	1	0.55	7.5
23	Myricetin	318.24	80.06	151.59	0.79	−3.01	Soluble	Low	No	No	CYP1A2, CYP3A4	1	0.55	3.27
24	N-methylcoclaurine	299.36	90.52	52.93	2.59	−3.82	Soluble	High	Yes	Yes	CYP2D6	0	0.55	2.92
25	Nornuciferine	281.35	87.06	30.49	3.01	−3.74	Soluble	High	Yes	Yes	CYP1A2, CYP2D6, CYP3A4	0	0.55	3.35
26	Reticuline	329.39	97.01	62.16	2.6	−3.88	Soluble	High	Yes	Yes	CYP2D6	0	0.55	3.07
27	Sabadelin	530.86	167.55	38.83	10.35	−10.03	Insoluble	Low	No	Yes	NONE	2	0.17	6.47
28	Xylomatenin	622.92	181.81	116.45	7.47	−7.43	Poorly soluble	Low	No	No	CYP3A4	1	0.55	7.58

Table 1. Predicted pharmacokinetics properties of selected ligands

Ligands

Predicted ADME Parameter from SWISSADME

TPSA (Å²)

Log P

ESOL Log S

ESOL Class

GIA

BBB permeant

P-gp

CYPs inhibitor

Lip

Physicochemical properties: Molecular weight (MW), Molar Refractivity (MR), Total polar surface area (TPSA). Lipophilicity: Consensus Log P. Water Solubility: ESOL Log S, ESOL Class. Pharmacokinetics: Gastrointestinal absorption (GIA), Blood-brain barrier (BBB), P-glycoprotein (P-gp) substrate, Inhibition of Cytochrome P450 (CYPs) type CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4. Druglikeness: Lipinski (Lip), Bioavailability Score (BS), Medicinal Chemistry: Synthetic accessibility (SA).

Annonacin

596.88

172.67

116.45

6.92

−7.13

Poorly soluble

Low

CYP3A4

0.55

7.36

Annonacin-10-one

594.86

171.71

113.29

6.83

−6.8

Poorly soluble

Low

Yes

CYP3A4

0.55

7.18

Annonaine

265.31

80.13

30.49

2.88

−3.71

Soluble

High

Yes

CYP1A2, CYP2D6, CYP3A4

0.55

3.36

Cis-Annoreticuin

596.88

172.67

116.45

6.94

−7.13

Poorly soluble

Low

CYP3A4

0.55

7.36

Asimilobine

267.32

82.59

41.49

2.65

−3.54

Soluble

High

Yes

CYP1A2, CYP2D6, CYP3A4

0.55

3.24

Cinnamic acid

148.16

43.11

37.3

1.79

−2.37

Soluble

High

Yes

NONE

0.85

1.67

Corossolone

578.86

170.55

93.06

7.75

−7.66

Poorly soluble

Low

Yes

NONE

0.17

6.9

Coumaric acid

164.16

45.13

57.53

1.26

−2.02

Soluble

High

Yes

NONE

0.85

1.61

Dicaffeoylquinic acid

516.45

126.9

211.28

0.91

−3.65

Soluble

Low

Yes

NONE

0.11

4.83

Dihydrokaempferol-hexoside

450.39

105.12

186.37

−0.5

−2.8

Soluble

Low

Yes

NONE

0.17

5.24

Epoxymurin-A

530.86

167.55

38.83

10.35

−10.03

Insoluble

Low

Yes

NONE

0.17

6.47

Epoxymurin-B

530.86

167.55

38.83

10.37

−10.03

Insoluble

Low

Yes

NONE

0.17

6.47

Epomusenin-A

558.92

177.17

38.83

11.09

−10.75

Insoluble

Low

Yes

NONE

0.17

6.73

Epomusenin-B

558.92

177.17

38.83

11.08

−10.75

Insoluble

Low

Yes

NONE

0.17

6.73

Fisetin

286.24

76.01

111.13

1.55

−3.35

Soluble

High

CYP1A2, CYP2D6, CYP3A4

0.55

3.16

Kaempferol

286.24

76.01

111.13

1.58

−3.31

Soluble

High

CYP1A2, CYP2D6, CYP3A4

0.55

3.14

Kaempferol 3-O-rutinoside

594.52

139.36

249.2

−0.73

−3.42

Soluble

Low

Yes

NONE

0.17

6.48

Luteolin 3,7-di-O-glucoside

610.52

140.26

269.43

−1.49

−3.22

Soluble

Low

Yes

NONE

0.17

6.39

Montecristin

574.92

180.05

66.76

9.92

−9.64

Poorly soluble

Low

Yes

NONE

0.17

6.82

Morin

302.24

78.03

131.36

1.2

−3.16

Soluble

High

CYP1A2, CYP2D6, CYP3A4

0.55

3.25

Muricatetrocin B

470.64

129.41

116.45

3.8

−4.1

Moderately soluble

High

CYP3A4

0.55

6.21

Muricatocin A

612.88

173.84

136.68

6.17

−6.61

Poorly soluble

Low

CYP3A4

0.55

7.5

Myricetin

318.24

80.06

151.59

0.79

−3.01

Soluble

Low

CYP1A2, CYP3A4

0.55

3.27

N-methylcoclaurine

299.36

90.52

52.93

2.59

−3.82

Soluble

High

Yes

CYP2D6

0.55

2.92

Nornuciferine

281.35

87.06

30.49

3.01

−3.74

Soluble

High

Yes

CYP1A2, CYP2D6, CYP3A4

0.55

3.35

Reticuline

329.39

97.01

62.16

2.6

−3.88

Soluble

High

Yes

CYP2D6

0.55

3.07

Sabadelin

530.86

167.55

38.83

10.35

−10.03

Insoluble

Low

Yes

NONE

0.17

6.47

Xylomatenin

622.92

181.81

116.45

7.47

−7.43

Poorly soluble

Low

CYP3A4

0.55

7.58

**Table 2.** Target prediction results
SN	Compound	Target gene code	Target description	p-value	MTC
1	Annonacin	PDCD4	Programmed cell death protein 4	4.236e-74	0.36
PTGER2	Prostaglandin E2 receptor EP2 subtype	1.586e-06	0.32
2	Annonacin-10-one	PDCD4	Programmed cell death protein 4	6.804e-70	0.33
IL6ST	Interleukin-6 receptor subunit beta	4.887e-23	0.30
PPM1A	Protein phosphatase 1A	7.318e-23	0.28
SLCO2A1	Solute carrier organic anion transporter family member 2A1	8.104e-18	0.28
3	Annonaine	TAS1R1	Taste receptor type 1 member 1	3.462e-06	0.29
4	Cis-Annoreticuin	PDCD4	Programmed cell death protein 4	4.236e-74	0.36
5	Asimilobine	TH	Tyrosine 3-monooxygenase	1.001e-39	0.32
DRD1	D(1A) dopamine receptor	1.11e-16	0.39
MMP26	Matrix metalloproteinase-26	1.384e-07	0.32
6	Cinnamic acid	HCAR2	Hydroxycarboxylic acid receptor 2	8.423e-10	1.00
NR0B2	Nuclear receptor subfamily 0 group B member 2	9.432e-46	0.31
GPR183	G-protein coupled receptor 183	2.941e-42	0.39
SENP2	Sentrin-specific protease 2	3.568e-41	0.33
CYP1B1	Cytochrome P450 1B1	6.792e-40	0.48
RCOR3	REST corepressor 3	1.157e-39	0.31
PAM	Peptidyl-glycine alpha-amidating monooxygenase	1.372e-38	0.52
CHRNA10	Neuronal acetylcholine receptor subunit alpha-10	1.097e-35	0.28
7	Corossolone	PDCD4	Programmed cell death protein 4	3.7e-33	0.30
PPM1A	Protein phosphatase 1A	2.063e-23	0.29
8	Coumaric acid	CA3	Carbonic anhydrase 3	1.966e-29	1.00
CA6	Carbonic anhydrase 6	4.201e-29	1.00
CA5B	Carbonic anhydrase 5B, mitochondrial	5.523e-27	1.00
CA5A	Carbonic anhydrase 5A, mitochondrial	2.466e-26	1.00
CA14	Carbonic anhydrase 14	7.845e-21	1.00
CA7	Carbonic anhydrase 7	9.975e-20	1.00
AKR1B1	Aldo-keto reductase family 1 member B1	5.551e-16	1.00
9	Dicaffeoylquinic acid	NSD2	Histone-lysine N-methyltransferase NSD2	0.0008982	1.00
CXCL12	Stromal cell-derived factor 1	1.437e-76	0.38
NR0B2	Nuclear receptor subfamily 0 group B member 2	3.814e-47	0.33
MYOC	Myocilin	1.277e-31	0.39
10	Dihydrokaempferol-hexoside	TOP1	DNA topoisomerase 1	6.893e-61	0.36
SLC5A2	Sodium/glucose cotransporter 2	8.932e-58	0.43
SLC28A3	Solute carrier family 28 member 3	9.656e-53	0.42
TYR	Tyrosinase	5.641e-36	0.42
IL2	Interleukin-2	5.276e-30	0.40
CBS	Cystathionine beta-synthase	2.038e-27	0.48
11	Epoxymurin-A	PDCD4	Programmed cell death protein 4	1.016e-45	0.36
LYPLA2	Acyl-protein thioesterase 2	1.4e-22	0.29
12	Epoxymurin-B	PDCD4	Programmed cell death protein 4	1.016e-45	0.36
LYPLA2	Acyl-protein thioesterase 2	1.4e-22	0.29
13	Epomusenin-A	PDCD4	Programmed cell death protein 4	1.016e-45	0.36
LYPLA2	Acyl-protein thioesterase 2	1.4e-22	0.29
14	Epomusenin-B	PDCD4	Programmed cell death protein 4	1.016e-45	0.36
LYPLA2	Acyl-protein thioesterase 2	1.4e-22	0.29
15	Fisetin	ELAVL3	ELAV-like protein 3	2.048e-65	0.66
HSD17B3	Testosterone 17-beta-dehydrogenase 3	1.047e-52	0.43
ALDH2	Aldehyde dehydrogenase, mitochondrial	4.45e-50	0.41
CYP1B1	Cytochrome P450 1B1	6.994e-39	0.66
16	Kaempferol	ELAVL3	ELAV-like protein 3	1.407e-81	0.78
PTPRS	Receptor-type tyrosine-protein phosphatase S	5.492e-59	0.75
CBS	Cystathionine beta-synthase	9.017e-51	0.45
CREB1	Cyclic AMP-responsive element-binding protein 1	5.513e-45	0.30
P4HB	Protein disulfide-isomerase	6.101e-41	0.52
17	Kaempferol 3-O-rutinoside	P4HB	Protein disulfide-isomerase	3.535e-71	1.00
SLC28A3	Solute carrier family 28 member 3	1.353e-43	0.35
ELAVL3	ELAV-like protein 3	2.773e-43	0.39
IL2	Interleukin-2	1.262e-31	0.42
TYR	Tyrosinase	9.763e-30	0.34
XDH	Xanthine dehydrogenase/oxidase	1.157e-25	0.65
18	Luteolin 3,7-di-O-glucoside	CREB1	Cyclic AMP-responsive element-binding protein 1	5.266e-69	0.35
SLC5A2	Sodium/glucose cotransporter 2	3.962e-60	0.41
SLC28A3	Solute carrier family 28 member 3	3.077e-50	0.40
IL2	Interleukin-2	5.836e-40	0.89
19	Montecristin	PDCD4	Programmed cell death protein 4	1.128e-77	0.41
SLCO2A1	Solute carrier organic anion transporter family member 2A1	2.172e-38	0.32
POLH	DNA polymerase eta	3.331e-16	0.31
20	Morin	PTPRS	Receptor-type tyrosine-protein phosphatase S	6.131e-56	1.00
MPG	DNA-3-methyladenine glycosylase	1.089e-50	1.00
DAPK1	Death-associated protein kinase 1	1.344e-21	1.00
ELAVL3	ELAV-like protein 3	8.402e-82	0.68
P4HB	Protein disulfide-isomerase	3.742e-36	0.44
21	Muricatetrocin B	PDCD4	Programmed cell death protein 4	2.688e-59	0.33
22	Muricatocin A	PDCD4	Programmed cell death protein 4	1.009e-81	0.40
23	Myricetin	ELAVL3	ELAV-like protein 3	2.196e-101	1.00
XDH	Xanthine dehydrogenase/oxidase	5.844e-36	1.00
24	N-methylcoclaurine	DRD1	D(1A) dopamine receptor	1.982e-95	0.58
DHCR7	7-dehydrocholesterol reductase	2.187e-43	0.50
TUBB1	Tubulin beta-1 chain	5.991e-26	0.35
ABCB1	ATP-dependent translocase ABCB1	9.037e-26	0.45
SLC18A2	Synaptic vesicular amine transporter	4.29e-24	0.35
25	Nornuciferine	TUBB	Tubulin beta chain	4.386e-25	0.31
26	Reticuline	DRD1	D(1A) dopamine receptor	9.256e-98	0.56
DHCR7	7-dehydrocholesterol reductase	3.993e-44	0.51
TUBB1	Tubulin beta-1 chain	1.432e-43	0.40
FSHR	Follicle-stimulating hormone receptor	1.151e-29	0.30
NDUFA1	NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1	5.531e-17	0.32
27	Sabadelin	PDCD4	Programmed cell death protein 4	1.016e-45	0.36
LYPLA2	Acyl-protein thioesterase 2	1.4e-22	0.29
28	Xylomatenin	PDCD4	Programmed cell death protein 4	9.378e-70	0.41
SLCO2A1	Solute carrier organic anion transporter family member 2A1	1.494e-36	0.31

Table 2. Target prediction results

Compound

Target gene code

Target description

p-value

MTC

Annonacin

PDCD4

Programmed cell death protein 4

4.236e-74

0.36

PTGER2

Prostaglandin E2 receptor EP2 subtype

1.586e-06

0.32

Annonacin-10-one

PDCD4

Programmed cell death protein 4

6.804e-70

0.33

IL6ST

Interleukin-6 receptor subunit beta

4.887e-23

0.30

PPM1A

Protein phosphatase 1A

7.318e-23

0.28

SLCO2A1

Solute carrier organic anion transporter family member 2A1

8.104e-18

0.28

Annonaine

TAS1R1

Taste receptor type 1 member 1

3.462e-06

0.29

Cis-Annoreticuin

PDCD4

Programmed cell death protein 4

4.236e-74

0.36

Asimilobine

Tyrosine 3-monooxygenase

1.001e-39

0.32

DRD1

D(1A) dopamine receptor

1.11e-16

0.39

MMP26

Matrix metalloproteinase-26

1.384e-07

0.32

Cinnamic acid

HCAR2

Hydroxycarboxylic acid receptor 2

8.423e-10

1.00

NR0B2

Nuclear receptor subfamily 0 group B member 2

9.432e-46

0.31

GPR183

G-protein coupled receptor 183

2.941e-42

0.39

SENP2

Sentrin-specific protease 2

3.568e-41

0.33

CYP1B1

Cytochrome P450 1B1

6.792e-40

0.48

RCOR3

REST corepressor 3

1.157e-39

0.31

PAM

Peptidyl-glycine alpha-amidating monooxygenase

1.372e-38

0.52

CHRNA10

Neuronal acetylcholine receptor subunit alpha-10

1.097e-35

0.28

Corossolone

PDCD4

Programmed cell death protein 4

3.7e-33

0.30

PPM1A

Protein phosphatase 1A

2.063e-23

0.29

Coumaric acid

CA3

Carbonic anhydrase 3

1.966e-29

1.00

CA6

Carbonic anhydrase 6

4.201e-29

1.00

CA5B

Carbonic anhydrase 5B, mitochondrial

5.523e-27

1.00

CA5A

Carbonic anhydrase 5A, mitochondrial

2.466e-26

1.00

CA14

Carbonic anhydrase 14

7.845e-21

1.00

CA7

Carbonic anhydrase 7

9.975e-20

1.00

AKR1B1

Aldo-keto reductase family 1 member B1

5.551e-16

1.00

Dicaffeoylquinic acid

NSD2

Histone-lysine N-methyltransferase NSD2

0.0008982

1.00

CXCL12

Stromal cell-derived factor 1

1.437e-76

0.38

NR0B2

Nuclear receptor subfamily 0 group B member 2

3.814e-47

0.33

MYOC

Myocilin

1.277e-31

0.39

Dihydrokaempferol-hexoside

TOP1

DNA topoisomerase 1

6.893e-61

0.36

SLC5A2

Sodium/glucose cotransporter 2

8.932e-58

0.43

SLC28A3

Solute carrier family 28 member 3

9.656e-53

0.42

TYR

Tyrosinase

5.641e-36

0.42

IL2

Interleukin-2

5.276e-30

0.40

CBS

Cystathionine beta-synthase

2.038e-27

0.48

Epoxymurin-A

PDCD4

Programmed cell death protein 4

1.016e-45

0.36

LYPLA2

Acyl-protein thioesterase 2

1.4e-22

0.29

Epoxymurin-B

PDCD4

Programmed cell death protein 4

1.016e-45

0.36

LYPLA2

Acyl-protein thioesterase 2

1.4e-22

0.29

Epomusenin-A

PDCD4

Programmed cell death protein 4

1.016e-45

0.36

LYPLA2

Acyl-protein thioesterase 2

1.4e-22

0.29

Epomusenin-B

PDCD4

Programmed cell death protein 4

1.016e-45

0.36

LYPLA2

Acyl-protein thioesterase 2

1.4e-22

0.29

Fisetin

ELAVL3

ELAV-like protein 3

2.048e-65

0.66

HSD17B3

Testosterone 17-beta-dehydrogenase 3

1.047e-52

0.43

ALDH2

Aldehyde dehydrogenase, mitochondrial

4.45e-50

0.41

CYP1B1

Cytochrome P450 1B1

6.994e-39

0.66

Kaempferol

ELAVL3

ELAV-like protein 3

1.407e-81

0.78

PTPRS

Receptor-type tyrosine-protein phosphatase S

5.492e-59

0.75

CBS

Cystathionine beta-synthase

9.017e-51

0.45

CREB1

Cyclic AMP-responsive element-binding protein 1

5.513e-45

0.30

P4HB

Protein disulfide-isomerase

6.101e-41

0.52

Kaempferol 3-O-rutinoside

P4HB

Protein disulfide-isomerase

3.535e-71

1.00

SLC28A3

Solute carrier family 28 member 3

1.353e-43

0.35

ELAVL3

ELAV-like protein 3

2.773e-43

0.39

IL2

Interleukin-2

1.262e-31

0.42

TYR

Tyrosinase

9.763e-30

0.34

XDH

Xanthine dehydrogenase/oxidase

1.157e-25

0.65

Luteolin 3,7-di-O-glucoside

CREB1

Cyclic AMP-responsive element-binding protein 1

5.266e-69

0.35

SLC5A2

Sodium/glucose cotransporter 2

3.962e-60

0.41

SLC28A3

Solute carrier family 28 member 3

3.077e-50

0.40

IL2

Interleukin-2

5.836e-40

0.89

Montecristin

PDCD4

Programmed cell death protein 4

1.128e-77

0.41

SLCO2A1

Solute carrier organic anion transporter family member 2A1

2.172e-38

0.32

POLH

DNA polymerase eta

3.331e-16

0.31

Morin

PTPRS

Receptor-type tyrosine-protein phosphatase S

6.131e-56

1.00

MPG

DNA-3-methyladenine glycosylase

1.089e-50

1.00

DAPK1

Death-associated protein kinase 1

1.344e-21

1.00

ELAVL3

ELAV-like protein 3

8.402e-82

0.68

P4HB

Protein disulfide-isomerase

3.742e-36

0.44

Muricatetrocin B

PDCD4

Programmed cell death protein 4

2.688e-59

0.33

Muricatocin A

PDCD4

Programmed cell death protein 4

1.009e-81

0.40

Myricetin

ELAVL3

ELAV-like protein 3

2.196e-101

1.00

XDH

Xanthine dehydrogenase/oxidase

5.844e-36

1.00

N-methylcoclaurine

DRD1

D(1A) dopamine receptor

1.982e-95

0.58

DHCR7

7-dehydrocholesterol reductase

2.187e-43

0.50

TUBB1

Tubulin beta-1 chain

5.991e-26

0.35

ABCB1

ATP-dependent translocase ABCB1

9.037e-26

0.45

SLC18A2

Synaptic vesicular amine transporter

4.29e-24

0.35

Nornuciferine

TUBB

Tubulin beta chain

4.386e-25

0.31

Reticuline

DRD1

D(1A) dopamine receptor

9.256e-98

0.56

DHCR7

7-dehydrocholesterol reductase

3.993e-44

0.51

TUBB1

Tubulin beta-1 chain

1.432e-43

0.40

FSHR

Follicle-stimulating hormone receptor

1.151e-29

0.30

NDUFA1

NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1

5.531e-17

0.32

Sabadelin

PDCD4

Programmed cell death protein 4

1.016e-45

0.36

LYPLA2

Acyl-protein thioesterase 2

1.4e-22

0.29

Xylomatenin

PDCD4

Programmed cell death protein 4

9.378e-70

0.41

SLCO2A1

Solute carrier organic anion transporter family member 2A1

1.494e-36

0.31

**Table 3.** Molecular docking results
S.N	Phytochemicals	PubChem CID	PDCD4 (AlphaFold ID: AF-Q53EL6) Binding Affinity ΔG (kcal.mol⁻¹)
Docking parameter: PDCD4 [spacing: 0.525, box size: 126 × 126 × 126, center: −9.248 × 0.161 × 1.314].
1	Annonacin	354398	−4.741
2	Annonacin-10-one	180161	−4.591
3	Annonaine	160597	−7.294
4	Cis-Annoreticuin	72778911	−4.869
5	Asimilobine	160875	−6.409
6	Cinnamic acid	444539	−3.96
7	Corossolone	4366126	−4.615
8	Coumaric acid	637542	−5.183
9	Dicaffeoylquinic acid	12358846	−6.775
10	Dihydrokaempferol-hexoside	10478918	−7.012
11	Epoxymurin-A	5281161	−4.416
12	Epoxymurin-B	131752983	−3.789
13	Epomusenin-A	10507050	−3.842
14	Epomusenin-B	10698082	−3.614
15	Fisetin	5281614	−6.979
16	Kaempferol	5280863	−6.749
17	Kaempferol 3-O-rutinoside	5318767	−6.629
18	Luteolin 3,7-di-O-glucoside	5490298	−7.65
19	Montecristin	102083640	−3.861
20	Morin	5281670	−6.884
21	Muricatetrocin B	393472	−5.362
22	Muricatocin A	133072	−5.191
23	Myricetin	5281672	−6.538
24	N-methylcoclaurine	440595	−5.946
25	Nornuciferine	41169	−6.226
26	Reticuline	439653	−5.907
27	Sabadelin	101006011	−3.426
28	Xylomatenin	10484035	−4.5
STD	Dexamethasone	5743	−6.682

Table 3. Molecular docking results

S.N

Phytochemicals

PubChem CID

PDCD4 (AlphaFold ID: AF-Q53EL6) Binding Affinity ΔG (kcal.mol⁻¹)

Docking parameter: PDCD4 [spacing: 0.525, box size: 126 × 126 × 126, center: −9.248 × 0.161 × 1.314].

Annonacin

354398

−4.741

Annonacin-10-one

180161

−4.591

Annonaine

160597

−7.294

Cis-Annoreticuin

72778911

−4.869

Asimilobine

160875

−6.409

Cinnamic acid

444539

−3.96

Corossolone

4366126

−4.615

Coumaric acid

637542

−5.183

Dicaffeoylquinic acid

12358846

−6.775

Dihydrokaempferol-hexoside

10478918

−7.012

Epoxymurin-A

5281161

−4.416

Epoxymurin-B

131752983

−3.789

Epomusenin-A

10507050

−3.842

Epomusenin-B

10698082

−3.614

Fisetin

5281614

−6.979

Kaempferol

5280863

−6.749

Kaempferol 3-O-rutinoside

5318767

−6.629

Luteolin 3,7-di-O-glucoside

5490298

−7.65

Montecristin

102083640

−3.861

Morin

5281670

−6.884

Muricatetrocin B

393472

−5.362

Muricatocin A

133072

−5.191

Myricetin

5281672

−6.538

N-methylcoclaurine

440595

−5.946

Nornuciferine

41169

−6.226

Reticuline

439653

−5.907

Sabadelin

101006011

−3.426

Xylomatenin

10484035

−4.5

STD

Dexamethasone

5743

−6.682

**Table 4.** Prime MMGBSA binding energy of interaction of PDCD4 with Annonaine and Dexamethasone respectively, before and after molecular dynamics simulation.
Complex	Simulation Time (ns)	MMGBSA ΔG^bind (kcal.mol⁻¹)
Covalent: Covalent binding energy; Coulomb: Coulomb energy; Lipo: Lipophilic energy; Hbond: Hydrogen bonding energy; Packing: Pi-pi packing correction; Solv GB: Generalized Born electrostatic solvation energy; vdW: Van der Waals energy; Total: Total energy (Prime energy).
Annonaine and PDCD4	0	−64.428	2.791	−0.60	−14.323	−0.541	69.403	−28.149	−35.851
100	−52.471	1.676	−0.797	−15.184	−1.519	52.998	−23.720	−39.019
Dexamethasone and PDCD4	0	0.913	0.092	−0.420	−7.605	0	11.380	−32.850	−28.489
100	−4.693	−0.012	−0.027	−8.555	0	15.696	−30.694	−28.284

Table 4. Prime MMGBSA binding energy of interaction of PDCD4 with Annonaine and Dexamethasone respectively, before and after molecular dynamics simulation.

Complex

Simulation Time (ns)

MMGBSA ΔG^bind (kcal.mol⁻¹)

Coulomb

Covalent

Hbond

Lipo

Packing

Solv_GB

vdW

G^bind (Total)

Covalent: Covalent binding energy; Coulomb: Coulomb energy; Lipo: Lipophilic energy; Hbond: Hydrogen bonding energy; Packing: Pi-pi packing correction; Solv GB: Generalized Born electrostatic solvation energy; vdW: Van der Waals energy; Total: Total energy (Prime energy).

Annonaine and PDCD4

−64.428

2.791

−0.60

−14.323

−0.541

69.403

−28.149

−35.851

100

−52.471

1.676

−0.797

−15.184

−1.519

52.998

−23.720

−39.019

Dexamethasone and PDCD4

0.913

0.092

−0.420

−7.605

11.380

−32.850

−28.489

100

−4.693

−0.012

−0.027

−8.555

15.696

−30.694

−28.284