In silico Docking Approach of Coumarin Derivatives as an Aromatase Antagonist

Reshma Thomas, R. Hari, Josna Joy, Saranya Krishnan, Swathy A.N, Sruthy. S. Nair,

Asha Asokan Manakadan, Sathianarayanan, Saranya T.S*

Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham University, AIMS Health Sciences Campus, Ponekkara P. O., Kochi – 682041, Kerala, India

*Corresponding Author E-mail: saranyats19347@aims.amrita.edu

ABSTRACT:

Coumarins are pharmacologically active moiety well known for their wide variety of activities. Coumarin is the combination of benzene and pyrone ring and it belongs to benzo pyrone family. It is available from plants, microorganisms etc. Depending on various substitutions on different positions of coumarin, we get different pharmacological properties like anticancer, antioxidant, antifungal, anti-inflammatory, antiviral, anticoagulant etc. The purpose of this study is to carry out the docking studies of coumarin derivatives containing electrophilic and nucleophilic substitutions with the anticancer target aromatase by using Arguslab version 4.0.1. Fifty four lead molecules were designed and their docking scores were compared with the standard drug Gefitinib. The validation of ligands were performed using Lipinski rule of five. It was observed that nineteen ligands showed better docking score than the standard drug Gefitinib. Phytoconstituents like Isofraxidin, Scopoletin and umbelliferone from Compositae family, which were the source of coumarin nucleus were also taken for the docking analysis. It was observed that most of the lead molecules showed higher docking score than the phytoconstituents.

KEYWORDS: Coumarin, Aromatase, Docking, Arguslab, Gefitinib

INTRODUCTION:

Coumarin belongs to benzo pyron family with class name of coumaro, the vernacular name of tonka bean (Dipeteryx odorata willd, Fabaceae) from which coumarin was isolated in 1820 ^[1-3]. Various coumarin derivatives are present in plant kingdom, coumarins are mostly found in essential oils found in cinnamon bark, cassia leaf, lavnder etc. They are also obtained from fruits like bilberry, cloudberry etc. Most of the coumarins are present in higher plants, and widely available from Rutaceae and umbilliferone family ^[4]. Some of the members of coumarins are also discovered from microorganisms, like novobiocin and coumermycin from streptomyces and aflatoxin from Aspergillus species.

Coumarins can be synthesized in lab by various chemical reactions and depending upon different substitutions on coumarin it will produce derivatives with different biological activities like antimicrobial, antioxidant, anticoagulant, antiviral, anti-inflammatory, anticancer etc^[5-13]. Aromatase is an enzyme belonging to cytochrome p450 family. It has been observed that the main cause of breast cancer is increase in the level of estrogen. Researches in this field denotes that, coumarin have inhibitory activity on aromatase, which is a key enzyme in the biosynthesis of estrogen from androgen^[14]. Therefore, the objective of the study was to develop coumarin derivatives and to check their potency and toxicity against the known cancer targets.

Fig 1: Chemical structure of coumarin nucleus

MATERIALS AND METHODS:

Fifty four lead molecules were designed by using chemsketch by giving substitutions on 3^rd, 4^th, 5^th, 6^th, 7^th and 8^th positions of coumarin nucleus as shown in fig:1. In this study gefitinib was selected as the reference drug, which is an anticancer drug ^[15].

Docking study:

Molecular docking:

Docking is a method, which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Here the docking was performed using the software Argus lab 4.0.1. All the water molecules in the protein were removed and docked with designed ligands to check the affinity expressed in terms of the docking score. Then the ligand score was compared with the score of reference drug to determine the efficiency of the designed lead molecules.

RESULTS AND DISCUSSION:

Table 1. Analysis of Lipinski Rule of Five for novel proposed analogues of coumarin

Sl. No	Name of the compound	Molecular weight	No. of Hba	No. of Hbd	C log p	No of Rot. b	No. of violations
1	3- Bromo Coumarin	225.041	2	0	2.751	0	0
2	4- Bromo Coumain	225.041	2	0	2.751	0	0
3	5-Bromo Coumarin	225.041	2	0	2.775	0	0
4	6-Bromo Coumarin	225.041	2	0	2.799	0	0
5	7-Bromo Coumarin	225.041	2	0	2.799	0	0
6	8-Bromo Coumarin	225.041	2	0	2.775	0	0
7	3-Chloro Coumarin	180.59	2	0	2.62	0	0
8	4- Chloro Coumarin	180.59	2	0	2.62	0	0
9	5-Chloro Coumarin	180.59	2	0	2.64	0	0
10	6-Chloro Coumarin	180.59	2	0	2.668	0	0
11	7-Chloro Coumarin	180.59	2	0	2.668	0	0
12	8-Chloro Coumarin	180.59	2	0	2.64	0	0
13	3- Fluoro Coumarin	164.135	2	0	1.133	0	0
14	4- Fluoro Coumarin	164.135	2	0	2.105	0	0
15	5- Fluoro Coumarin	164.135	2	0	2.129	0	0
16	6- Fluoro Coumarin	164.135	2	0	1.181	0	0
17	7- Fluoro Coumarin	164.135	2	0	2.153	0	0
18	8- Fluoro Coumarin	164.135	2	0	2.129	0	0
19	3- Iodo Coumarin	272.041	2	0	3.025	0	0
20	4-Iodo Coumarin	272.041	2	0	3.025	0	0
21	5-Iodo Coumarin	272.041	2	0	3.049	0	0
22	6-Iodo Coumarin	272.04	2	0	3.073	0	0
23	7-Iodo Coumarin	272.04	2	0	3.073	0	0
24	8-Iodo Coumarin	272.041	2	0	3.049	0	0
25	3-Hydroxy Coumarin	162.14	3	1	1.723	0	0
26	4- Hydroxy Coumarin	162.14	3	1	1.723	0	0
27	5 -Hydroxy Coumarin	162.14	3	1	1.747	0	0
28	6 -Hydroxy Coumarin	162.14	3	1	1.511	0	0
29	7-Hydroxy Coumarin	162.14	3	1	1.511	0	0
30	8-Hydroxy Coumarin	162.14	2	0	1.511	0	0
31	3-MethoxyCoumarin	176.171	3	0	1.998	0	0
32	4-Methoxy Coumarin	176.171	3	0	1.998	0	0
33	5-Methoxy Coumarin	176.171	3	0	2.022	0	0
34	6-Methoxy Coumarin	176.171	3	0	2.046	0	0
35	7-Methoxy Coumarin	176.171	3	0	2.046	0	0
36	8-MethoxyCoumarin	176.171	3	0	2.022	0	0
37	3- Ethoxy Coumarin	190.18	3	0	2.374	0	0
38	4-Ethoxy Coumarin	190.18	3	0	2.374	0	0
39	5-Ethoxy Coumarin	190.18	3	0	2.398	0	0
40	6-Ethoxy Coumarin	190.18	3	0	2.422	0	0
41	7-Ethoxy Coumarin	190.18	3	0	2.422	0	0
42	8-Ethoxy Coumarin	190.18	3	0	2.422	0	0
43	3- Nitro Coumarin	191.14	5	0	1.901	0	0
44	4 -Nitro Coumarin	191.14	5	0	1.901	0	0
45	5- Nitro Coumarin	191.14	5	0	1.901	0	0
46	6 -Nitro Coumarin	191.14	5	0	1.901	0	0
47	7 -Nitro Coumarin	191.14	5	0	1.901	0	0
48	8 -Nitro Coumarin	191.14	5	0	1.901	0	0
49	2oxo-2H-chromene-3-carbaldehyde	174.155	3	0	1.732	0	0
50	2oxo-2H-chromene-4-carbaldehyde	174.155	3	0	1.732	0	0
51	2oxo-2H-chromene-5-carbaldehyde	174.155	3	0	1.732	0	0
52	2oxo-2H-chromene-6-carbaldehyde	174.155	3	0	1.732	0	0
53	2oxo-2H-chromene-7-carbaldehyde	174.155	3	0	1.732	0	0
54	2oxo-2H-chromene-8-carbaldehyde	174.155	3	0	1.732	0	0
	Phytoconstituents
1	Isofraxidin	222.2	5	1	1.54	2	0
2	Scopoletin	192.17	4	1	1.33	1	0
3	Umbilliserone	176.17	3	1	1.89	0	0

Selection of target:

The target selected was the aromatase inhibitor having PDB id 3S7S as the target ^[16].

Preparation of ligands:

The ligands were designed and their smiles notations were obtained from ChemSketch, which is a chemically intelligent drawing, interface freeware developed by Advanced Chemistry Department. The designed ligands were saved in PDB format, which is acceptable to all docking software.

Validation of ligands

The molecular properties based on Lipinski rule of five and the drug ADME were checked using the software Molinspiration, the results are compiled in the Table 1 and 2.

The results of the validation of ligands shows that the values of all fifty four compounds and three phytoconstituents based on molecular weight is less than 500 Daltons, number of hydrogen bond donors and hydrogen bond acceptors are below 5 and 10, partition coefficient lies within the limits of 5. The results shows that there is no violation of Lipinski rule of five.

Bioactivity study:

Table 2. Bioactivity results of proposed analogues of coumarin

Sl no	Name of compound	GPCR ligand	Ion channel modulator	Kinase inhibitor	Nuclear receptor ligand	Protease inhibitor	Enzyme inhibitor
1	3-Bromo Coumarin	-1.37	-0.83	-1.29	-1.21	-1.35	-0.58
2	4-Bromo Coumain	-1.29	-0.93	-1.19	-1.10	-1.36	-0.54
3	5-Bromo Coumarin	-1.34	-0.97	-1.29	-1.35	-1.44	-0.57
4	6-Bromo Coumarin	-1.63	-1.52	-1.46	-1.54	-1.55	-0.66
5	7-Bromo Coumarin	-1.63	-0.91	-1.61	-1.63	-1.68	-1.69
6	8-Bromo Coumarin	-1.49	-1.03	-1.59	-1.42	-1.43	-0.53
7	3-Chloro Coumarin	-1.45	-1	-1.48	-1.27	-1.33	-1.58
8	4-Chloro Coumarin	-1.29	-1.65	-1.26	-1.08	-1.31	-1.55
9	5-Chloro Coumarin	-1.30	--0.67	-1.36	-1.29	-1.36	-0.57
10	6-Chloro Coumarin	-1.27	-0.75	-1.40	-1.26	-1.32	-1.53
11	7-Chloro Coumarin	-1.24	-0.65	--1.53	-1.21	-1.35	-0.53
12	8-Chloro Coumarin	-1.45	-1	-1.48	-1.27	-1.33	-.0.52
13	3- Fluoro Coumarin	-1.13	-0.71	-1.32	-1.23	-1.37	-0.60
14	4- Fluoro Coumarin	-1.13	-0.69	-1.06	-0.92	-1.22	-0.46
15	5- Fluoro Coumarin	-1.13	-0.71	-1.14	--1.12	-1.29	-0.40
16	6- Fluoro Coumarin	-1.20	-0.75	-1.30	-1.15	-1.33	-0.47
17	7- Fluoro Coumarin	-1.09	-0.65	-1.25	-1.26	-1.27	-0.46
18	8- Fluoro Coumarin	-1.29	-0.67	-1.30	-1.01	-1.33	-0.42
19	3-Iodo Coumarin	-1.24	-0.60	-1.17	-0.96-1.	-1.27	-0.53
20	4-Iodo Coumarin	-1.16	-0.67	-1.07	-0.99	-1.23	-0.57
21	5-Iodo Coumarin	-1.26	-0.70	-1.04	-1.19	-1.29	-0.60
22	6-Iodo Coumarin	-1.31	-0.69	-1.26	-1.19	--1.44	-0.59
23	7-Iodo Coumarin	-1.31	-0.69	-1.26	-1.19	-1.44	-0.59
24	8-Iodo Coumarin	-1.24	-0.71	-1.32	-0.23	-1.37	-0.60
25	3-Hydroxy Coumarin	-1.11	-0.59	-1.13	-0.78	-1.14	-0.23
26	4-Hydroxy Coumarin	-1.29	-0.49	-1.51	-1.02	-1.08	-0.27
27	5-Hydroxy Coumarin	-1.21	-0.59	-1.32	-1.12	-1.17	-0.28
28	6-Hydroxy Coumarin	-1.15	-0.64	-1.22	-0.69	-1.26	-0.23
29	7-Hydroxy Coumarin	-1.22	-0.72	-1.30	-0.92	-1.30	-0.35
30	8-Hydroxy Coumarin	-1.02	-0.64	-1.30	-1.11	-1.12	-0.24
31	3-MethoxyCoumarin	-1.08	-0.67-	-1.05	-0.86	-1.12	-0.31
32	4-Methoxy Coumarin	-1.22	-0.58	-1.24	-1.12	-1.08	-0.41
33	5-Methoxy Coumarin	-1.15	-0.67	-1.25	-1.21	-1.16	-0.42
34	6-Methoxy Coumarin	-1.15	-0.67	-1.25	-1.21	-1.16	-1.42
35	7-Methoxy coumarin	-1.19	-0.51	-1.27	-1.19	-1.26	-0.48
36	8-MethoxyCoumarin	-1.19	-0.91	-1.27	-1.19	-1.28	-0.48
37	3- EthoxyCoumarin	-1.14	-0.53	-1.18	-0.93	-0.99	-0.39
38	4-EthoxyCoumarin	-1.09	-0.70	-1.15	-0.85	-1.14	-0.42
39	5-EthoxyCoumarin	-1.15	-0.77	-1.22	-0.67	-1.18	-0.45
40	6-EthoxyCoumarin	-1.09	-0.70	-1.15	-0.85	-1.14	-0.42
41	7-EthoxyCoumarin	-1.15	-0.77	-1.22	-0.67	-1.18	-0.65
42	8-EthoxyCoumarin	-1.11	-0.84	-1.21	-0.99	-1.17	-0.46
43	3-Nitro Coumarin	-1.07	-0.67	-1.21	-0.99	-1.20	-0.47
44	4-Nitro Coumarin	-1.15	-0.64	-0.94	-0.93	-1.42	-1.40
45	5-Nitro Coumarin	-1.22	-0.58	-1.12	-1.03	-1.38	-0.48
46	6-Nitro Coumarin	-1.21	-0.63	-1.24	-1.08	-1.22	-0.46
47	7-Nitro Coumarin	-1.29	-0.66	-1.37	-1.10	-1.28	-0.54
48	8-Nitro Coumarin	-1.06	-0.65	-0.96	-1.15	-1.13	-0.36
49	2oxo-2H-chromene-3-carbaldehyde	-1.19	-0.84	-1.24	-0.76	-1.19	-0.42
50	2oxo-2H-chromene-4-carbaldehyde	-1.36	-0.94	-1.15	-0.66	-1.46	-0.48
51	2oxo-2H-chromene-5-carbaldehyde	-1.21	-0.84	-1.12	-0.82	-1.40	-0.46
52	2oxo-2H-chromene-6-carbaldehyde	-1.26	-0.78	-1.29	-0.94	-1.40	-0.461
53	2oxo-2H-chromene-7-carbaldehyde	-1.29	-0.71	-1.35	-1.01	-1.44	-0.50
54 1 2 3	2oxo-2H-chromene-8-carbaldehyde Phytoconstituents Isofraxidin Scopoletin Umbilliserone	-1.21 -0.88 -1.00 -1.31	-0.87 -0.34 -0.65 -1.10	-1.25 -0.76 -0.95 -1.18	-1.01 -0.76 -0.81 -0.62	-1.45 -0.94 -1.16 -139	-0.51 -0.06 -0.24 -0.40

Docking Analysis:

The docking scores were obtained for the designed coumarin derivatives against aromatase receptor and the scores are as given in Table .3

Table 3. Docking scores for 54 novel proposed analogues of coumarin by using Arguslab 4.0.1

Sl No:	Substitution	Docking Score (kcal/mol)
1	3-Bromo Coumarin	-9.7
2	4- Bromo Coumain	-9.7
3	5-Bromo Coumarin	-9.6
4	6-Bromo Coumarin	-9.6
5	7-Bromo Coumarin	-9.2
6	8-Bromo Coumarin	-9.5
7	3-Chloro Coumarin	-9.4
8	4-Chloro Coumarin	-8.9
9	5-Chloro Coumarin	-9.7
10	6-Chloro Coumarin	-9.3
11	7-Chloro Coumarin	-9.2
12	8-Chloro Coumarin	-9.4
13	3- Fluoro Coumarin	-9
14	4-Fluoro Coumarin	-8.4
15	5- Fluoro Coumarin	-8.9
16	6- Fluoro Coumarin	-8.6
17	7- Fluoro Coumarin	-8.8
18	8- Fluoro Coumarin	-8.9
19	3-Iodo Coumarin	-9.8
20	4-Iodo Coumarin	-9.4
21	5-Iodo Coumarin	-9.5
22	6-Iodo Coumarin	-9.6
23	7-Iodo Coumarin	-9.1
24	8-Iodo Coumarin	-9.1
25	3-Hydroxy Coumarin	-8.6
26	4-Hydroxy Coumarin	-8.3
27	5-Hydroxy Coumarin	-8.2
28	6-Hydroxy Coumarin	-8
29	7-Hydroxy Coumarin	-7.8
30	8-Hydroxy Coumarin	-8.2
31	3-Methoxy Coumarin	-8
32	4-Methoxy Coumarin	-8.29
33	5-Methoxy Coumarin	-8.34
34	6-Methoxy Coumarin	-7.4
35	7-Methoxy Coumarin	-7.8
36	8-Methoxy Coumarin	-8.2
37	3- Ethoxy Coumarin	-9.1
38	4-Ethoxy Coumarin	-8.2
39	5-Ethoxy Coumarin	-8.1
40	6-Ethoxy Coumarin	-8.3
41	7-Ethoxy Coumarin	-8.2
42	8-Ethoxy Coumarin	-8.1
43	3- Nitro Coumarin	-8.7
44	4- Nitro Coumarin	-8.4
45	5- Nitro Coumarin	-7.93
46	6- Nitro Coumarin	-7.94
47	7- Nitro Coumarin	-8.32
48	8- Nitro Coumarin	-8.64
49	2oxo-2H-chromene-3-carbaldehyde	-8.40
50	2oxo-2H-chromene-4-carbaldehyde	-8.25
51	2oxo-2H-chromene-5-carbaldehyde	-8.69
52	2oxo-2H-chromene-6-carbaldehyde	-8.07
53	2oxo-2H-chromene-7-carbaldehyde	-8.27
54	2oxo-2H-chromene-8-carbaldehyde	-8.51
55	Gefitinib(standard drug)	-8.9

The docking scores were obtained for the phytoconstituents having coumarin nucleus against aromatase receptor and the scores are as given in Table. 4

Table. 4 Docking scores of phytoconstituents having coumarin nucleus using argus lab 4.0.1

Sl. No	Phytoconstituent	Docking Score(Kcal/mol)
1	Isofraxidin	-6.8
2	Scopoletin	-7.16
3	Umbillierone	-8.4

It was observed that among bromine substituted coumarins, 3-bromo coumarin and 4-bromo coumarin showed best docking score (Fig. 2 and 3)

Fig. 2-bromo coumarin

Fig. 3 bromo coumarin

Among the chlorine-substituted coumarin 5-chloro coumarin shows best docking score (fig.4)

Fig.4-chloro coumarin

Among the fluorine substituted coumarin 3- Fluoro coumarin showed best docking score (fig.5)

Fig.5- Fluoro coumarin

Among the iodine substituted coumarin 3-iodo coumarin showed best docking score (fig.6)

Fig.6- iodo coumarin

Among the hydroxyl substituted coumarin 3-hydroxy coumarin showed best docking score (fig.7)

Fig.7-hydroxy coumarin

Among the methoxy substituted coumarin 5-methoxy coumarin showed best docking score (fig.8)

Fig.8-methoxy coumarin

Among the ethoxy substituted coumarin 3-ethoxy coumarin showed best docking score (fig.9)

Fig.9-ethoxy coumarin

Among the nitro substituted coumarin 3-nitro coumarin showed best docking score (fig.10)

Fig.10 3-nitro coumarin

Among the aldehyde substituted coumarin 2 oxo 2H –chromene- 5 carbaldehyde showed best docking score (fig.11)

Fig.11 2oxo-2H-chromene-5 carbaldehyde

Among the fifty four compounds nineteen designed analogues of coumarin shows good docking score compared to the reference drug Gefitinib, which is a drug used in the treatment of breast cancer. Among 19 derivatives 3-iodo coumarin showed best docking score than the reference drug gefitinib.

CONCLUSION:

The docking studies conducted in coumarin for its anti cancer properties was successful and from that we came to a conclusion that coumarin derivatives with iodine substitution at the third position of the heterocyclic ring showed good docking score compared to the standard drug gefitinib and three phytoconstituent having coumarin pharmacophore. From the present study we could also finalise that the substitutions at the third position of coumarin ring with several electron withdrawing groups such as bromo, fluoro, and nitro and electron releasing group such as hydroxyl substitution demonstrate best affinity with the aromatase receptors. The phytoconstituents of coumarin shows less docking score as compared with these ligands.

ACKNOWLEDGEMENTS:

We are thankful to Department of Chemistry, Amrita School of Pharmacy, Amrita Viswa Vidyapeetham University, for providing necessary facilities for the study.

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Received on 24.10.2015 Modified on 04.11.2015

Accepted on 21.11.2015 © RJPT All right reserved

Research J. Pharm. and Tech. 8(12): Dec., 2015; Page 1673-1678

DOI: 10.5958/0974-360X.2015.00302.9