MOLECULAR DOCKING ANALYSIS OF HETEROCYCLIC LIGANDS TARGETING NUDT5 PROTEIN IN BREAST CANCER

MOLECULAR DOCKING ANALYSIS OF HETEROCYCLIC LIGANDS TARGETING NUDT5 PROTEIN IN BREAST CANCER

R. Govinda Rajan, S. Udhaya Vani, A. P. S. M. Krishna *, Ch. Dhanalakshmi Manimadhuri, G. Harika and S. K. Nujhat Aara

Department of Pharmaceutical Chemistry, Hindu College of Pharmacy, Guntur, Andhra Pradesh, India.

ABSTRACT: Breast cancer is the most common malignancy affecting women worldwide. Molecular docking   is an important computational technique in drug discovery interaction between ligands and target proteins. In present study docking analysis binding affinity of 51 heterocyclic ligands against the breast cancer target protein NUDT5 (PDB ID:5NWH) are nucleotide- metabolizing enzymes (NUDIX) hydrolases. It plays a major role in hormone- dependent gene regulation and proliferation in breast cancer cells. The heterocyclic ligands docking analysis were analyzed by Autodock 4.0.1. The docking was validated by re docking co-crystallized inhibitor 9CH into active binding site of NUDT5 protein and evaluated binding energy, RMSD values and molecular interactions. The results were found ligand “GR39 exhibited the lowest binding energy” (-14.12kcal/mol), when compared with reference inhibitor 9CH [-10.59kcal/mol] and standard drugs like STD1 Tamoxifen (-9.65), STD2 Cyclophosphamide (-5.83), STD3 Doxorubicin (-11.74). However the present study is limited to molecular docking analyis. Further studies include in-vitro, in-vivo, ADME and cytotoxicity studies.

Keywords: Breast cancer, Molecular docking and NUDT5 protein

INTRODUCTION: Breast cancer is a malignant tumor that develops in the breast tissues, primarily in the ducts or lobules. It is the most frequently diagnosed cancer among women globally and accounts for a significant proportion of cancer-related deaths ¹. It is a heterogenous disease characterized by the molecular subtypes and multiple histological include Ductal carcinoma in situ and Invasive ductal carcinoma most common (80%) ².

At the molecular level, breast cancer is classified based on receptor status into Hormone receptor- positive and Triple-negative breast cancer. Breast cancer progression involves complex biological process such as Metastasis is primary cause of mortality, occurring years after initial treatment due to residual cancer stem cells and micro-environmental interactions ³.

Molecular docking is widely used in structure-based drug design to screen compounds and optimize drug candidates before experimental testing. The protein NUDT5 (NUDIX hydrolase 5) PDB ID:5NWH is a member of Nudix family of nucleotide-metabolizing enzymes. It functions primarily as an ADP-ribose pyrophosphatase, catalyzing the conversion of ADP-ribose into AMP OR ATP depending on cellular conditions. ATP plays Chromatin remodeling, Gene transcription and Hormone-dependent signaling pathways Fig. 1. This ATP production is particularly important in progesterone and estrogen signaling in breast cancer cells, linking metabolism directly to gene regulation ⁴. To overcome the problem and side effects of cancer, the present marketed drugs showing various adverse reactions, during treatments. In view of that, we want to develop new entities for the treatment of breast cancer cells ⁵.

FIG. 1: DEVELOPMENT OF POTENT NUDT5 INHIBITORS FROM A HIGH-THROUGHPUT SCREENING CAMPAIGN. A REPRESENTATION OF THE ENZYME-COUPLED MALACHITE GREEN ASSAY (MG ASSAY). ADPR IS HYDROLYZED TO AMP AND R5P BY NUDT5, THEN R5P IS CONVERTED TO FREE INORGANIC PHOSPHATE DETECTED BY THE MALACHITE GREEN REAGENT ⁵

MATERIALS AND METHODS:

Softwares: Chemdraw 8.0, Chemspider, Protein Data Bank, Pub Meb, Autodock 4.0.1, Discovery Studio V24, Crystal Protein-PDB CODE:5NWH Fig. 2 ⁶.

FIG. 2: CRYSTAL PROTEIN STRUCTURE OF 5NWH

Ligands:

Standard Ligand: Inhibitor (9CH), STDI (Tamoxifen), STD2 (cyclophosphamide), STD3 (Doxorubicin) ⁷.

Test Ligand: 51 selected ligands of various heterocyclic derivatives were collected from thesis ⁸.

The 51 ligands were collected from various literatures, based on  antioxidant activty, the selected ligands pharmacophores nucleus were presence in selected ligands  such as chromen 2-one, Tetrahydropyrimide,-1H-pyrrole, 1,5 benzodiazepene, 1,4 benzodiazepene, pyrazinyl, pyrrolidine-1-yl, biphenyl, 1,3,5 triazine, 2H-chromen-3-yl, quinoline, phenoxyphenyl, 1-2—hydroxyphenyl, pyrimidin, tiazine, and imadazo [2,1-b] [1,3,4]thiadiazole ⁹.

Protein Data Bank Information of 5NWH:

Classification: Hydrolase Organism(s): Homo sapiens Expression System: Escherichia coli ¹⁰.

Mutation(s): NO

Study of Molecular Docking:

Protein Preparation: Macromolecule was downloaded from protein data bank website (RCSB PDB) ¹⁰ Download the macromolecule in PDB formate ¹¹ open discovery studio for protein cleaning, ligand molecules, water molecules and other ions were removed using discovery studio. Open autodock 4.0.1 set preference and make default. Edit option and delete water, under edit select hydrogen and add polar hydrogen only and add kollman charges then check total residues and save molecule in PDBQT format.

Ligand Preparation: Structures of 51 selected ligand molecules, standard and reference inhibitor were drawn by using chemdraw 8.0 software ¹². Save the structures in mol format. Covert the mol format structures to pdb format by using BIOVIA ¹³. Retrieve the standard ligand molecules from chemspider website (http://www.chemspider.com/) and download the 3d structure of inhibitor from the protein data bank ¹⁴.

Molecular Docking: The ligand prepared and docked against protein using autodock 4.0.1. Output -lamarckian GA -save the file in DPF format. Launch the auto dock. Open the DLG file in the folder and check the lowest binding energy, runs, RMSD and estimated inhibition constant ¹⁵.

Visualization: Open the PDBQT saved file in discovery studioand draw the 2D and 3D diagram ¹⁶.

Docking Validation: Docking validation was performed by re-docking the co-crystallized inhibitor 9CH into the active site of the NUDT5 protein (PDB ID: 5NWH) using AutoDock 4.0.1. The reference inhibitor showed a binding energy of -10.59 kcal/mol with an RMSD value of 1.557 Å and inhibition constant of 17.30 nM, indicating reliable docking accuracy. The ligand exhibited significant interactions with key active-site residues including TRP A28, TRP B46, ARG A51, GLU A166, and GLY B135. Since the RMSD value was below 2 Å, the docking protocol was considered validated and suitable for further docking studies ^{15, 16}.

RESULTS AND DISCUSSION: It is of interest to design inhibitors for the breast cancer target NUDT5 using molecular docking based virtual screening followed by molecular docking ¹⁷.

STD1 (Tamoxifen) was shown more binding energy (-9.65), when compared with selected ligands of GR01, GR02, GR03, GR04, GR05, GR06, GR07, GR08, GR09, GR10, GR11, GR12, GR13, and GR1. Reference inhibitor (9CH) was shown more binding energy (-10.59), when compared with selected ligands of GR03, GR04, GR05, GR06, GR08, GR12, GR16, GR21, GR25, GR26, GR28, GR37, GR38, GR39, GR46, and GR47 respectively.

For docking results, amino acid residues linked with Reference inhibitor (9CH) binding position in the receptor at TRP A 28 (Pi-Pi Stacked Bond), TRP B 46 (Pi-Pi stacked bond), THR B 45 (Pi-Pi Stacked Bond), GLU B 47 (Carbon Hydrogen Bond), ARG A 51 (Conventional Hydrogen bond), GLU A 166 (Carbon Hydrogen Bond), GLY B 135 (Carbon Hydrogen Bond), ALA A 96 (Pi Alkyl Bond), ILE A 141 (Alkyl Bond). The Pose Run, RMSD value and the Inhibition Constant for Reference inhibitor (9CH) was found 41, 1.557 and 17.30 nM respectively.

GR16, GR17, GR18, GR19, GR20, GR21, GR22, GR23, GR25, GR26, GR28, GR30, GR37, GR38, GR39, GR41, GR44, GR46, GR47, GR49 Respectively: For docking results, amino acid residues with STD1 (Tamoxifen) binding position in the receptor at TRP A 28 (Pi-Pi T shaped bond), TRP B 46(Pi-Pi Stacked Bond), ARG A 51(Pi Alkyl bond), LEU A 98(Carbon Hydrogen Bond), GLU A 166 (Carbon Hydrogen Bond). The Pose Run, RMSD value and the Inhibition Constant for STD1 were found 6, 20.390 and 85.01nM respectively ¹⁸.

STD2 (cyclophosphamide) was shown more binding energy (-5.83), when compared with All the selected ligands. For docking results, amino acid residues with STD2 (cyclophosphamide) binding position in the receptor at TRP B 46 (Pi cation bond), ARG A 51 (Conventional Hydrogen Bond), GLY B 135 (Pi Cation Bond), TRP A 28 (Pi Alkyl bond). The Pose Run, RMSD value and the Inhibition Constant for STD2 were found 34, 19.875 and 53,670 NM respectively ¹⁹.

STD3 (Doxorubicin) was shown more binding energy (-11.74), when compared with selected ligands of GR25, GR37, GR38, GR39 respectively. For docking results, amino acid residues with STD3 (doxorubicin) binding position in the receptor at ASP B 164 (Conventional Hydrogen Bond), GLU B 166(Carbon Hydrogen Bond), GLY B 165 (Conventional Hydrogen Bond), TYR A 36 (Conventional Hydrogen Bond), TRP A 46(Pi-Pi T shaped bond), PHE B 165 (Carbon Hydrogen Bond), VAL B 168 (Alkyl bond), ARG B 51(Conventional Hydrogen Bond). The Pose Run, RMSD value and the Inhibition Constant for STD3 (doxorubicin) were found 47, 20.366 and 2.50nM respectively ²⁰.

Grid values of co-ordinates axis X, Y, Z are 2.086, -9.948, -17.613

Spacing of atoms 0.375

Angle of Dimensions X, Y, Z – 126,126,126

Docking Studies: The selected ligands, standards and inhibitors interaction with protein were performed by using Autodock 4.0.1 and the output of docking results was calculated from dlg file Table 2. In comparison binding energy with Reference Inhibitor (-10.59), STD1 (-9.65), STD2 (-5.83), STD3 (-11.74); the selected ligand GR39 was showed lowest energy (-14.12). For docking results, amino acid residues with selected ligand GR39 binding position in the receptor at TRP B 46 (Napthyl ring, Pi-Pi stacked bond), ARG A 51(phenyl ethyl ring, Pi Cation bond),  ARG A 84(Pi Cation bond), GLN B 15(Amino phenyl ring, Conventional Hydrogen Bond ), TYR B 36(Phenyl ring, Pi Donar Hydrogen Bond). The Pose Run, RMSD value and the Inhibition Constant for selected ligand GR39 were found 47, 30.726 and 44.59nM respectively. Fig. 3 showing the 2D and 3D structures of GR39 selected ligand interaction with the crystal protein 5NWH ^21-22.

FIG. 3: 3D AND 2D STRUCTURES OF GR39 (E) (-1-(4-(4-(4-AMINOPHENYLAMINO)-6-(NAPHTHALEN-1-YLOXY)-1,3,5-TRIAZINE-2-YLAMINO) PHENYL)-3-(4-ETHYLPHENYL) PROP-2-EN-1-ONE)

FIG. 4: 3D AND 2D STRUCTURE OF INHIBITOR (9CH)

FIG. 5: 3D AND 2D STRUCTURE OF STD1 (TAMOXIFEN)

FIG. 6: 3D AND 2D STRUCTURE OF STD2 (CYCLOPHOSPHAMIDE)

FIG. 7: 3D AND 2D STRUCTURE OF STD3 (DOXORUBICIN)

TABLE 1: CHEMICAL PROPERTIES OF SELECTED LIGANDS, STANDARD DRUGS AND INHIBITOR’S

S. no.	Code	Structurere	IUPAC Name	Molecular formula	Mol. wt
1	GR01		3-[6-(4-methylphenyl)imidazole[2,1-6][1,3,4]thiadiazol-2yl]-2H-Chromen-2-one	C20H13N3O2S	359.4
2	GR02		3-(6-phenyl)imidazo(2,1-6)(1,3,4)thiadiazol-2-yl)2H-chromen-2-one	C19H11N3O2S	345.37
3	GR03		6-(4methoxyphenyl)-2-{[(4-methyl-2-oxo-2H-chromen-7yl)oxy]methyl}imidazo(2,1-6)(1,3,4)thiadazole-5carbaldehyde	C23H17N3O5S	447.46
4	GR04		2-((4-chloro-2-oxo-2H-chromen-7-yloxy)methyl)-6-(4-chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde	C21H11Cl2N3O4S	472.3
5	GR05		2-{[(4-methyl-2-oxo-2H-chromen-7-yl)oxy]methyl}-6-phenylimidazo(2,1-6)(1,3,4)thiadazole-5-carbaldehyde	C22H15N3O4S	417.44
6	GR06		Methyl 1-[(19z,20z)-3,4-bis(2-nitrobenzylidene)-2,5-dioxopyrolidin-1-yl-)-1,2,3,4-tetrahydro-6-methyl-4-phenyl pyrimide-5-carboxylate	C31H23N5O9	609.54
7	GRO7		Methyl 1-[(19z,20z)-3,4-bis(4-(dimethylamino)benzylidene)-2,5-dioxopyrolidin-1-yl-)-1,2,3,4-tetrahydro-6-methyl-4-phenyl pyrimide-5-carboxylated	C35H35N5O5	605.68
8	GR08		N-1-(4-[(3-(E)-1-[4-(dimethylamino)phenyl]methylidene-4(z)-1[4(dimethylamino)phenyl]methylidene-2,5-dioxotetrahydro-1H-1-pyrrolyl)amino]sulphonyl-phenyl)acetamide	C35H35N5O5	605.68
9	GR09		2,3-dihydro-2-4-diphenyl-1H-1,5benzodiazepine	C21H18N2	298.38
10	GR10		4-[2-3-dihydro-4-phenyl-1H-1,5benzodiazepine-2yl)phenol	C21H18N2O	314.38
11	GR11		2-(4-chlorophenyl)-2,3-dihydro-4-phenyl-H-1,5benzodiazepine	C21H17ClN2	332.83
12	GR12		4-((E)-2,3-dihydro-4-phenyl-1H-1,5benzodiazepine-2-yl)-N,Ndimethyl benzene amine	C23H23N3	341.45
13	GR13		7-isopropyl-5-phenyl-1H-1,4benzodiazepine-2(3H)-one	C18H18N2O	278.35
14	GR14		5-phenyl-1H-naptho[1,2][1,4]diazepine-2(3H)one	C19H14N2O	286.33
15	GR15		8-methoxy-5-phenyl-1H-1,4benzodiazepine-2(3H)-one	C16H14N2O2	266.29
16	GR16		(N1-(2-pyrazinyl)-(E)-3-[4-({[(2-pyridalamino)carbonyl]amino}sulfonyl)phenyl]-2-propenamide]	C19H16N6O4S	424.43
17	GR17		(N1-(2-pyrazinyl)-(E)-3-[4-({[(2-pyrazinylamino)carbonyl]amino}phenyl]-2-propenamide]	C18H15N7O4S	425.42
18	GR18		(N1-(2-pyrazinyl)-2-hydroxy-[4-({[(2-pyrazinylamino)carbonyl]amino}sulfonyl)benzamide	C17H14N6O5S	414.4
19	GR19		(N1-(2-pyrazinyl)-2-hydroxy-[4-({[(2-pyrazinylamino)carbonyl]amino}sulfonyl)benzamide	C16H13N7O5S	415.38
20	GR20		1-(3z,4E)-3,4bis(4-chloro benylidene)-2,5-dioxopyrrolidin-1-yl) Thio urea	C19H13Cl2N3O2S	418.3
21	GR21		1-2,5-dioxo-3,4-bis(diphenylmethylene)pyrrolidine-1-yl)thiourea	C31H23N3O2S	501.6
22	GR22		(E)-1-([1,1,-biphenyl]-4-yl)-3-(4-cholor phenyl)prop-2-en-1-one	C21H15ClO	318.8
23	GR23		(E)-1-([1,1,-biphenyl]-4-yl)-3-(3-nitrophenyl)prop-2-en-1-one	C21H15NO3	329.35
24	GR24		1-([1,1-biphenyl]-4-yl)-2-(2-amino-4,5-dihydro-1H-imidazol-1-yl)ethan-1-on	C17H15N3OS	309.39
25	GR25		1-(4-[4-(4-nitrophenylamino)-6-(benzylamino)-1,3,5-triazin-2-ylamino)phenyl]ethanone	C24H21N7O3	455.47
26	GR26		N2-(3,4-dimethylphenyl)-N6-(2-nitrophenyl)-N4-(3-nitrophenyl)-1,3,5-triazine-2,4,6-triamine	C24H22N8O4	486.48
27	GR27		N-(3-(2-amino-4,5-dihydro oxazol-4-yl)-phenyl)-4,6-dichloro-1,3,5-triazin-2-amine	C12H10Cl2N6O	325.15
28	GR28		4,6-dichloro-N-(3-(4,5-dihydro-2-phenyloxazol-4-yl)phenyl)-1,3,5-triazin-2-amine	C18H13Cl2N5O	386.23
29	GR29		N-(4-(2-amino-4,5-dihydro oxazol-4-yl)-phenyl)-4,6-dichloro-1,3,5-triazin-2-amine	C12H10Cl2N6O	325.15
30	GR30		N-(4-(2-amino-4,5-dihydro thiazol-4-yl)-phenyl)-4,6-dichloro-1,3,5-triazin-2-amine	C12H10Cl2N6S	341.22
31	GR31		(2z)-ethyl3-(4-(4-benzylpiperazin-1-yl)-2-oxo-2H chromen-3-yl)-2-cyanoacrylate	C26H25N3O4	443.49
32	GR32		2-((4-morpholino-2-oxo-2H-chromen-3-yl)methylene)malononitrile	C17H13N3O3	307.3
33	GR33		Diethyl2-((2-oxo-4-(piperidine-1-yl)-2H-chromen-3-yl)methylene)malonate	C22H25NO6	399.44
34	GR34		6H-chromeno[4,3-b]quinolin-6-one	C16H9NO2	247.25
35	GR35		9-chloro-6H-chromeno[4,3-b]quinolin-6-one	C16H8ClNO2	281.69
36	GR36		6H-chromen[4,3-b]quinoline-6-one	C19H15NO2	289.33
37	GR37		(E)-1-(4-(methylamino)-6-(benzaldehyde-1-yloxy)-1,3,5-triazine-2-ylamino)phenyl)-3-(methoxyphenyl)prop-2-en-1-one	C27H23N5O4	481.5
38	GR38		(E)-1-(4-(methylamino)-6-(benzaldehyde-1-yloxy)-1,3,5-triazine-2-ylamino)phenyl)-3-(nitrophenyl)prop-2-en-1-one	C26H20N6O5	496.47
39	GR39		(E)-1-(4-(4-(4-aminophenylamino)-6-(naphthalen-1-yloxy)-1,3,5-triazine-2-ylamino)phenyl)-3-(4-ethylphenyl)prop-2-en-1-one	C36H30N6O2	578.66
40	GR40		1-(4-(4,6-dimethoxy-1,3,5-triazine-2-ylamino)phenyl)ethanone	C13H14N4O3	274.28
41	GR41		1-(4,6-bis(3-hydroxyphenoxy)-1,3,5-triazin-2-ylamino)-3-hydroxy-1-phenylpropan-2-one	C19H18N4O6S	430.43
42	GR42		1-(4-nitrophenyl)-3-(4-phenoxyphenyl)prop-2-en-1-one	C21H15NO4	345.35
43	GR43		3-(4-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one	C15H11ClO2	258.7
44	GR44		2-(2-hydrazino-6-(4-chlorophenyl)pyrimidin-4-yl)phenol	C16H13ClN4O	312.75
45	GR45		3-(4-(dimethylamino)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one	C17H17NO2	267.32
46	GR46		3-(4-(4-nitrophenylamine)-6-(4-dimethylamino)phenyl)-6H-1,3-thiazin-2-ylamino)-2-(furan-2-yl))imidazolidine-4-one	C25H25N7O4S	519.58
47	GR47		1-(4-phenylacetamido)-6-(4-hydroxyphenyl)-6H-1,3-thiazin-2-ylamino)-4-(4-(dimethylamino)phenyl)-3-chloroazetedin-2-one	C29H28ClN5O3S	562.08
48	GR48		1-(4-nitrophenyl)-3-(4-phenoxyphenyl)prop-2-en-1-one	C21H15NO4	345.35
49	GR49		3-(4-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one	C21H15NO4	345.35
50	GR50		2,6-bis(4-chlorophenyl) imidazo[2,1-b] [1,3,4]thiadiazole	C16H9Cl2N3S	346.23
51	GR51		4-(2-(4-aminophenyl) imidazo[2,1-b][1,3,4]thiadiazol-6-yl)phenol	C16H15N7O2	337.34
52	Inhibitor		7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-piperazin-1-yl-purine-2,6-dione	C20H20Cl2N8O3	491.33
53	STD1		2-{4-[(1Z)-1,2-Diphenyl-1-buten-1-yl]phenoxy}-N,N-dimethylethanamin	C26H29NO	371.51
54	STD2		2-(bis(2-chloroethyl)amino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide	C12H28Cl2N3O2P	348.25
55	STD3		(8S,10S)-10-{[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy}-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-tetracenedione	C27H29NO11	543.52

TABLE 2: DOCKING VALIDATION RESULTS OF SELECTED LIGANDS, STANDARD DRUGS AND INHIBITOR

CONCLUSION: Breast cancer is one of the most common types of malignancies in women in world wide. The risk of breast increases with age Between 45 to 50 in females. So we conducted docking studies on the marketed drugs, Reference Inhibitor with selected ligands on breast cancer crystal protein (PDB: 5NWH).

In this study the crystal structure of 5NWH receptor bound to 9CH was replaced with 51 selected ligands as potential target for breast Cancer. So among 51 selected ligands GR39 (-14.12) showed lowest binding energy compared with Reference Inhibitor (-10.59), STD1 (-9.65), STD2 (-5.83), STD3 (-11.74). In future, studies will be performed to establish the in-vitro, in-vivo on breast cancer cell lines.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: Nil 

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    How to cite this article:

    Rajan RG, Vani SU, Krishna APSM, Manimadhuri CD, Harika G and Aara SKN: Molecular docking analysis of heterocyclic ligands targeting NUDT5 protein in breast cancer. Int J Pharm Sci & Res 2026; 17(9): 2660-75. doi: 10.13040/IJPSR.0975-8232.17(9).2660-75.

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