Hybrid-based drug design of 1,2,3-triazole-pyrimidine-hybrid derivatives: Efficient inhibiting agents of mesenchymal–epithelial transition factor reducing gastric cancer cell growth

Abstract

Anti-gastric cancer activity of 18 synthesized compounds was studied using theoretical and computational method. The studied compounds were docked against mesenchymal–epithelial transition factor (PDB ID: 2wgj) and the obtained scoring was compared with the standard used. Thus, all the studied compounds were efficient than the standard (5-florouracil); also, A9 proved to be more effective than other studied compounds.

Keywords

1,2,3-triazole-pyrimidine-hybrid density functional theory mesenchymal–epithelial transition factor molecular docking quantitative structure–activity relationship

Introduction

Cancer, a malignant neoplasia is mostly originated as a narrowed infection, which over time spread all over the human body.^1,2 Many ailments in human body are signs for the existence of cancer such as lengthened cough, weight loss, rare blood loss, and bumps.³ More so, gastric cancer, a type of cancer is a nuisance which ensues in human gastrointestinal system.⁴ This type of cancer has been rated to be fifth among many other diseases that cause death globally.^5,6 More so, men are much more affected than women.^7,8

Moreover, mesenchymal–epithelial transition factor is one of the major and important measures for metastasis of several carcinomas.⁹ According to Christine et al.,¹⁰ mesenchymal–epithelial transition factor plays a serious role at the concluding phases of carcinoma development, and several types of cancer, such as breast cancer, gastric cancer, lung cancer, and melanoma, have revealed its upturned manifestation relative to average tissue.^11–14

The part taken by heterocycles in finding and development of innovative drugs is vital. Triazole and pyrimidine are two major compounds found in 1,2,3-triazole-pyrimidine-urea, and it has been discovered by several researcher to have anti-inflammatory, anticancer, antimicrobial, diuretics, analgesics, and antioxidant properties.^15–18

Thus, this work is aimed at calculating parameters with anti-gastric cancer properties as well as investigating non-bonding interactions (binding affinity, hydrophilic interactions, and hydrophobic interactions) between 1,2,3-triazole-pyrimidine hybrids derivatives (1,2,3-TPHDs) (Figure 1) and mesenchymal–epithelial transition factor (PDB ID: 2wgj) downloaded from protein data bank via molecular docking.¹⁹

Figure 1.

The schematic structures of 1,2,3-triazole-pyrimidine-urea hybrids derivatives.^20,21

Methodology

Biological activities of 1,2,3-triazole-pyrimidine-urea hybrids derivatives was investigated using Spartan 14 software²² for optimization and Discovery Studio client [ version v17.2.0.16349], AutoDock Tool [version 1.5.6 sep_17_14], and autodock_vina_1_1_2_win32 for molecular docking studies. The studied compounds were treated using Discovery Studio. In addition, AutoDock Tool helped in locating the active site of mesenchymal–epithelial transition factor (PDB ID: 2wgj), and the docking calculation was executed using AutoDock Vina. In addition, the inhibition constant was calculated using equation (1)

K_{i} = e^{- Δ G / R T}

(1)

Result and discussion

In this work, docking study was carried out on 18 molecular compounds in order to investigate the interactions between 1,2,3-TPHDs and mesenchymal–epithelial transition factor (PDB ID: 2wgj) and compared with 5-florouracil (5FU). As shown in Table 1, it was observed that all the studied compounds possess the ability to inhibit mesenchymal–epithelial transition factor more than the standard used. In addition, A9 with −10.1 kcal/mol proved to possess efficient and more capacity to inhibit than other studied compounds and this could be attributed to the presence of urea, trifluoromethane, and bromine attached to the parent structure (Figure 1 and 2).

Table 1.

Interactions between ligands and receptor (2wgj).

		Binding affinity (kcal/mol)	K_i (μM)	Residues involved between 1,2,3-triazole-pyrimidine hybrids and mesenchymal–epithelial transition factor complex
19	A1	−9.8	1.52 × 10⁷	HIS-1162, ASN-1167, GLY-1163, ASP-1231, ASP-1164, MET-1211, TYR-1230, VAL-1092, and ILE-1084
26	A2	−8.8	2.82 × 10⁶	ASP-1231, TYR-1230, MET-1211, ALA-1226, ALA-1221, ALA-1108, VAL-1157, MET-1160, ASP-1164, and ARG-1170
27	A3	−9.4	7.77 × 10⁶	TYR-1159, MET-1211, ALA-1108, LEU-1157, VAL-1092, TYR-1230, ASN-1167, ILE-1084, ARG-1208, HIS-1162, and ASP-1164
31	A4	−8.9	3.34 × 10⁶	ASP-1164, ILE-1084, ALA-1108, MET-1160, TYR-1159, TYR-1230, MET-1211, and VAL-1092
32	A5	−9.4	7.77 × 10⁶	ASP-1231, ASN-1167, ASP-1164, TYR-1230, MET-1211, GLY-1163, PHE-1168, and HIS-1174
33	A6	−9.7	1.29 × 10⁷	ILE-1084, TYR-1159, LYS-1161, GLY-1163, ASP-1164, TYR-1230, and ASP-1231
34	A7	−9.7	1.29 × 10⁷	ASP-1231, TYR-1230, ASP-1164, GLY-1163, LYS-1161, ILE-1084, and HIS-1162
35	A8	−9.6	1.09 × 10⁷	ILE-1084, ALA-1108, TYR-1159, MET-1160, MET-1211, TYR-1230, ASP-1231, ASP-1164, GLY-1163, and HIS-1162
37	A9	−10.1	2.53 × 10⁷	TYR-1230, ASP-1231, HIS-1174, ASP-1222, ALA-1221, ARG-1208, MET-1211, ASP-1164, and LYS-1161
41	A10	−9.0	3.96 × 10⁶	ASN-1167, ILE-1084, ARG-1086, GLY-1085, TYR-1230, MET-1211, LEU-1157, ALA-1226, VAL-1092, ALA-1108, and MET-1160
14	A11	−9.2	5.55 × 10⁶	ASN-1209, ARG-1086, ARG-1208, TYR-1230, VAL-1092, MET-1211, TYR-1159, ILE-1084, MET-1160, and ALA-1108
16	A12	−9.6	1.09 × 10⁷	LEU-1140, ALA-1221, VAL-1092, ALA-1108, ILE-1084, LEU-1157, TYR-1159 ASP-1164, TYR-1230, and MET-1211
17	A13	−9.1	4.68 × 10⁶	HIS-1162, GLY-1163, ALA-1108, VAL-1092, ALA-1226, ALA-1221, LEU-1140, LEU-1157, TYR-1230, MET-1211, ILE-1084, and ASP-1164
19	A14	−8.6	2.01 × 10⁶	ASN-1167, ASP-1164, LEU-1157, ALA-1221, ALA-1226, VAL-1092, LYS-1110, MET-1211, ALA-1108, ILE-1084, TYR-1230
22	A15	−9.3	6.57 × 10⁶	LYS-1161, HIS-1162, ILE-1084, TYR-1159, MET-1211, ALA-1221, TYR-1230, ALA-1180, VAL-1092, MET-1160, GLY-1163, and HIS-1162
23	A16	−9.9	1.80 × 10⁷	TYR-1230, ALA-1221, MET-1211, ILE-1084, ALA-1108, VAL-1092, LEU-1157, MET-1160, TYR-1159, ASN-1167, ARG-1170, ASP-1231, and ASP-1164
24	A17	−9.7	1.29 × 10⁷	ILE-1084, GLY-1163, VAL-1092, ALA-1226, ALA-1221, TYR-1230, MET-1211, and HIS-1162
34	A18	−9.7	1.29 × 10⁷	TYR-1230, HIS-1174, LEU-1157, LEU-1140, MET-1211, ALA-1221, ALA-1108, ILE-1084, and TYR-1159
	5FU	−5.0		SER-1236, VAL-1247, LYS-1248, and GLU-1233

The residues involved between studied compounds and 2wgj are HIS-1162, ASN-1167, GLY-1163, ASP-1231, ASP-1164, MET-1211, TYR-1230, VAL-1092, and ILE-1084 for A1; ASP-1231, TYR-1230, MET-1211, ALA-1226, ALA-1221, ALA-1108, VAL-1157, MET-1160, ASP-1164, and ARG-1170 for A2; TYR-1159, MET-1211, ALA-1108, LEU-1157, VAL-1092, TYR-1230, ASN-1167, ILE-1084, ARG-1208, HIS-1162, and ASP-1164 for A3; ASP-1164, ILE-1084, ALA-1108, MET-1160, TYR-1159, TYR-1230, MET-1211, and VAL-1092 for A4; ASP-1231, ASN-1167, ASP-1164, TYR-1230, MET-1211, GLY-1163, PHE-1168, and HIS-1174 for A5; ILE-1084, TYR-1159, LYS-1161, GLY-1163, ASP-1164, TYR-1230, and ASP-1231 for A6; ASP-1231, TYR-1230, ASP-1164, GLY-1163, LYS-1161, ILE-1084, and HIS-1162 for A7; ILE-1084, ALA-1108, TYR-1159, MET-1160, MET-1211, TYR-1230, ASP-1231, ASP-1164, GLY-1163, and HIS-1162 for A8; TYR-1230, ASP-1231, HIS-1174, ASP-1222, ALA-1221, ARG-1208, MET-1211, ASP-1164, and LYS-1161 for A9; ASN-1167, ILE-1084, ARG-1086, GLY-1085, TYR-1230, MET-1211, LEU-1157, ALA-1226, VAL-1092, ALA-1108, and MET-1160 for A10; ASN-1209, ARG-1086, ARG-1208, TYR-1230, VAL-1092, MET-1211, TYR-1159, ILE-1084, MET-1160, and ALA-1108 for A11; LEU-1140, ALA-1221, VAL-1092, ALA-1108, ILE-1084, LEU-1157, TYR-1159 ASP-1164, TYR-1230, and MET-1211 for A12; HIS-1162, GLY-1163, ALA-1108, VAL-1092, ALA-1226, ALA-1221, LEU-1140, LEU-1157, TYR-1230, MET-1211, ILE-1084, and ASP-1164 for A13; ASN-1167, ASP-1164, LEU-1157, ALA-1221, ALA-1226, VAL-1092, LYS-1110, MET-1211, ALA-1108, ILE-1084, and TYR-1230 for A14; LYS-1161, HIS-1162, ILE-1084, TYR-1159, MET-1211, ALA-1221, TYR-1230, ALA-1180, VAL-1092, MET-1160, GLY-1163, and HIS-1162 for A15; TYR-1230, ALA-1221, MET-1211, ILE-1084, ALA-1108, VAL-1092, LEU-1157, MET-1160, TYR-1159, ASN-1167, ARG-1170, ASP-1231, and ASP-1164 for A16; ILE-1084, GLY-1163, VAL-1092, ALA-1226, ALA-1221, TYR-1230, MET-1211, and HIS-1162 for A17; and TYR-1230, HIS-1174, LEU-1157, LEU-1140, MET-1211, ALA-1221, ALA-1108, ILE-1084, and TYR-1159 for A18 (Table 1).

Figure 2.

Molecular binding interaction between A9 and A16 with 2wgj.

Conclusion

Bioactivity of 18 sets of 1,2,3-TPHDs were studied by optimization using density functional theory method via 6-31+G(d, p) as basis set. Also, the docking study was observed to reveal the binding interaction between the studied compounds and the receptor. Also, the studied compounds were compared to the standard used (5FU) and the studied compounds proved to be more effective than the standard used. More so, compound A9 inhibited more effectively than other compounds and the standard used.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Abel Kolawole Oyebamiji

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