Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer

Maria Lopez-Ramos; Lauro Figueroa-Valverde; Marcela Rosas-Nexticapa; Magdalena Alvarez-Ramirez; Virginia Mateu-Armand; Regina Cauich-Carrillo

doi:10.51847/tFgoN65qlJ

ARTICLE

Year: 2024 | Volume: 13 | Issue: 5 | Page: 1-9 View issue

Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer

Maria Lopez-Ramos , Lauro Figueroa-Valverde^*✉ , Marcela Rosas-Nexticapa , Magdalena Alvarez-Ramirez , Virginia Mateu-Armand , Regina Cauich-Carrillo

Abstract

Several studies indicate that cancer development is associated with angiogenesis, which may be conditioned for VEGFR-1, VEGFR-2, and VEGFR-3 expression. It is noteworthy that some drugs, such as axitinib, cediranib, regorafenib, and sorafenib, have been used to treat cancer. Nevertheless, some of these drugs can induce different adverse effects, such as thrombocytopenia and leukopenia. Analyzing these data, this study aimed to evaluate whether bicyclo analogs (1-27) could couple with VEGFR-1, VEGFR-2, and VEGFR-3, utilizing 3hng, 2oh4, 4sbj proteins, axitinib, cediranib, regorafenib, and sorafenib as controls in DockingServer software. Results indicate that bicyclo derivatives could interact at different sites of the 3hng, 2oh4, and 4sbj proteins surface compared to axitinib, cediranib, regorafenib, and sorafenib. Other report suggest that the inhibition constant (Ki) related to the interaction of bicylo 1 and 5 with the 3hng protein surface was lower compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs. Besides, the Ki for coupling of 4, 7, 8, 10, 12, and 15-22 with 2oh4 protein surface was lower compared with cabozatinib and cediranib drugs. Finally, the results for the interaction of bicyclo-analogs 4, 6-8, 10, 12, 13, 16, 18-21, 23, 24, and 26 were lower compared with axitinib and cediranib drugs. All these data suggest that bicyclo derivatives 1, 4, 6-8, 10, 12, 13, 15-24, and 26 could be good anticancer agents by modulating the VEGFR-1, VEGFR-2, and VEGFR-3 expression.

Keywords: Cancer, Byciclo, Axitinib, Cediranib, VEGFR-1

Introduction

There are statistical data indicating that cancer is a public health worldwide, resulting in a decrease in the quality of life of the population.^[1-4] It noteworthy that there are some risk factors have been associated to involved in cancer development, such as hormone levels,^{[5, 6]} smoking,^[7] lifestyle,^[8] alcohol,^[9] dietary,^[10] and others. In addition, some reports indicate that different types of cancers are associated with the angiogenesis process,^[11-13] which is regulated by several biomolecules, such as vascular endothelial growth factor (VEGF), which plays an important role in cancer development.^[14] It is noteworthy that vascular endothelial growth factor expression can be produced by hypoxia,^[15] changes in pH,^[16] and interleukine-6 activation.^[17] This phenomenon may lead to interaction with some receptors involved in the endothelial cell surface, such as VEGF-R1, VEGF-R2, and VEGF-R3, which can be expressed in several cancers.^[18-20] For example, a study showed that VEGF can stimulate the formation of new lymphatic vessels in patients with gastric cancer through VEGFR-3 activation.^[21]

Furthermore, a report display that VEGFR-3 expression was positively correlated with metastatic lymph nodes.^[22] Other studies indicate that VEGFR-2 and VEGFR-3 are expressed in ovarian cancer patients using Western blott technique.^[23] Other data suggest that both VEGFR-1 and VEGFR-2 could be expressed in bladder squamous cell carcinoma cell lines throuhg the Western immunoblotting method.^[24] Furthermore, Nagano et al. (2019) disply that VEGFR-1 modulates epidermal growth factor receptor activity and can induce colon cancer cell growth by Western blot.^[25]

On the other hand, some pharmacological strategies have been used to control cancer cell growth using some VEGFR-1, VEGFR-2, and VEGFR-3 receptor inhibitors; for example, a study indicated that axitinib can decrease metastatic renal cell carcinoma through VEGFR-1, VEGFR-2, and VEGFR-3 receptors inhibition.^[26] Another study showed that Axitinib produces significant anticancer effects in epithelial ovarian cancer cells through inhibition of VEGF receptor signaling associated with cell proliferation, apoptosis, and migration.^[27] Other studies display that regorafenib (a VEGF receptor non-selective antagonist) increases survival in patients with refractory metastatic colorectal cancer.^[28] Besides, a report indicates that regorafenib combined with avelumab has antitumor activity in patients with biliary tract cancer;^[29] however, a study showed that regorafenib can induce adaptive resistance of colorectal cancer cells via inhibition of the vascular endothelial growth factor receptor.^[30] Furthermore, a study showed that the administration of sorafenib (a VEGFR-1, VEGFR-2, and VEGFR-3 inhibitor) can prolong survival in patients with advanced hepatocellular carcinoma.^[31] Other data showed that may act as a VEGFR-1 receptor inhibitor using AG1-G1-Flt-1 cells.^[32] All these data suggest that several anticancer drugs may act through VEGFR receptor inhibition; however, their interaction is not clear, perhaps this phenomenon could be due to experimental approaches used in the different studies performed. Analyzing these data, this study aimed to determine the possible interaction of twenty-seven bicyclo derivatives with VEGFR-1, VEGFR-2, and VEGFR-3 receptors using a theoretical model.

Materials and Methods

Figure 1 depicts the structure of twenty-seven bicyclo derivatives, which were utilized to ascertain if they may interact in the following ways with the VEGFR-1, VEGFR-2, and VEGFR-3 surface:

Figure 1. Chemical structure of bicyclo derivatives (1-27). Source: https://pubchem.ncbi.nlm.nih.gob

1 = 5-(4-methoxyphenyl)-2-(p-tolylsulfonyl)-2-aza-5-phosphabicyclo[2.2.1]heptane.

2 = 5-phenyl-2-(p-tolylsulfonyl)-2-aza-5-phosphabicyclo[2.2.1]heptane.

3 = (1S,2Z,4Z,7Z,9S)-bicyclo[7.2.0]undeca-2,4,7-triene-10,10,11,11-tetracarbonitrile.

4 = 1-(3-acetyl-1-bicyclo[1.1.1]pentanyl)ethanone.

5 = 1,2,3,4,5,6-hexachloro-7,7-dimethoxy-bicyclo[2.2.1]hept-2-ene.

6 = bicyclo[1.1.1]pentan-1-amine.

7 = 1-methoxybicyclo[2.2.2]oct-5-en-2-one.

8 = 2-isopropylsulfonylnorbornane.

9 = 2-(benzenesulfonyl)bicyclo[2.2.2]octane.

10 = 2,3-dibromonorbornane.

11 = 2,3-dichloronorbornane.

12 = 2-ethylnorbornane.

13 = 2-methylenenorbornane.

14 = 3,5,6-triphenyl-2,3,5,6-tetrazabicyclo[2.1.1]hex-1-ene.

15 = methyl N-[3-(benzyloxycarbonylamino)-1-bicyclo[1.1.1]pentanyl]-N-phenyl-carbamate.

16 = bicyclo[2.2.2]octane-1,4-diol.

17 = [3-(hydroxymethyl)-2-bicyclo[2.2.2]octanyl]methanol.

18 = bicyclo[2.2.1]hept-2-ene

19 = bicyclo[2.2.2]octan-2-ol.

20 = bicyclo[3.2.1]octan-6-one.

21 = bicyclo[3.2.1]octane-6,7-dione.

22 = bicyclo[3.3.1]nonan-3-one.

23 = norcaran-2-one.

24 = bicyclo[4.2.1]nona-2,4,7-triene.

25 = bicyclo[4.2.1]nonan-9-one.

26 = bicyclo[5.1.1]nonane-3,5-dione.

27 = bicyclo[5.3.1]undecan-9-one.

Ligand-protein complex

Coupling of bicyclo derivatives (1 to 30) with VEGFR1, VEGFR2, and VEGFR3 receptors, was determined using 2oh4,^[33] 3hng,^[34] and 4bsj^[35] proteins as chemical tools. Furthermore, compounds such as axinib, cediranib, cabozatinib, and sorafinib were used as controls in the DockingServer program.^[34]

Results and Discussion

Some theoretical methods, such as AutoDock, rDock, USFDock, and LeDock,^[36] have been used to determine the interaction of different drugs with some biomolecules. Other data indicate that DockingServer can be used to evaluate the interaction of some anticancer drugs; for example, a theoretical study showed the possibility that boswellic acid could act as an anticancer agent via interaction with CDK2 (cell division protein kinase 2) using ArgusLab 4.0.1 software.^[37] Besides, the DockingServer program was used to determine the interaction of some quinolone derivatives with RSK-4 (ribosomal S6 kinase 4); it is important to mention that these results suggest that quinolone derivatives could decrease cancer growth.^[38] Analyzing all these data, in this study the interaction of twenty-seven bicyclo derivatives with VEGFR-1, VEGFR-2, and VEGFR-3 was determined using 3hng, 2oh4, and 4bsj proteins in the DockingServer program. Besides, it is important to mention that axinib, cediranib, cabozatinib, pazonib, regorafenib, and sorafinib drugs were used as controls. The results showed different aminoacid residues of interaction bicyclo derivatives (compounds 1-27) with 3hng protein surface compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs (Table 1).

Table 1. Interaction of bicyclic derivatives (1-27), axitinib, cabozantinib, pazopanib, and regorafenib with amino acid residues of 3hng protein surface.
Compound	Aminoacid residues
Axitinib	Val₈₄₁; Glu₈₇₈; Ile₈₈₁; Leu₈₈₂; Val₈₉₁; Val₈₉₂; Leu₁₀₁₃; Cys₁₀₁₈; His₁₀₂₀; Leu₁₀₂₉; Ile₁₀₃₈; Cys₁₀₃₉; Asp₁₀₄₀; Phe₁₀₄
Cabozantinib	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu8₇₈; Ile₈₈₁; Leu₈₈₂; Val₈₉₂; Val₉₀₇; Val₉₀₉; Cys₁₀₁₈; His₁₀₂₀; Leu₁₀₂₉; Ile₁₀₃₈; Cys₁₀₃₉; Asp₁₀₄₀; Phe₁₀₄₁
Pazopanib	Leu₈₃₃; Glu₈₇₈; Leu₈₈₂; Val₈₉₂; Val₉₀₉; Tyr₉₁₁; Cys₉₁₂; His₁₀₂₀; Leu₁₀₂₉; Cys₁₀₃₉; Asp₁₀₄₀; Phe₁₀₄₁
Regorafenib	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Leu₈₈₂; Ile₈₈₅; Ile₈₈₁; Val₈₉₂; Val₉₀₇; Val₉₀₉; Cys₉₁₂; Leu₁₀₁₃; Cys₁₀₁₈; Ile₁₀₁₉; His₁₀₂₀; Leu₁₀₂₉; Asp₁₀₄₀; Phe₁₀₄₁
1	Val₈₄₁; Lys₈₆₁; Glu₈₇₈; Ile₈₈₁; Leu₈₈₂; Ile₈₈₅; Val₈₉₂; Leu₁₀₁₃; Cys₁₀₁₈; His₁₀₂₀; Ile₁₀₃₈; Cys₁₀₃₉; Asp₁₀₄₀; Phe₁₀₄₁
2	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Leu₈₈₂; Val₈₉₁; Val₈₉₂; Val₉₀₉; Cys₉₁₂; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
3	Glu₈₇₈; Ile₈₈₁; Leu₈₈₂; Ile₈₈₅; Val₈₉₁; Leu₁₀₁₃; Cys₁₀₁₈; His₁₀₂₀; Ile₁₀₃₈; Asp₁₀₄₀
4	Val₈₄₁; Lys₈₆₁; Glu₈₇₈; Leu₈₈₂; Val₈₉₂; Val₉₀₉; Asp₁₀₄₀
5	Asp₈₀₇; Thr₈₇₇; Glu₈₇₈; Ile₈₈₁; Ile₁₀₁₉; Arg₁₀₂₁; Asp₁₀₄₀
6	Cys₁₀₁₈; His₁₀₂₀; Asp₁₀₄₀
7	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Val₈₉₂; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
8	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Val₈₉₂; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉
9	Glu₈₇₈; Ile₈₈₁; Leu₈₈₂; Ile₈₈₅; Val₈₉₁; Leu₁₀₁₃; Cys₁₀₁₈; His₁₀₂₀; Ile₁₀₃₈; Asp₁₀₄₀
10	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
11	Val₈₄₁; Lys₈₆₁; Glu₈₇₈; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Asp₁₀₄₀;Phe₁₀₄₁
12	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₉₀₉; Cys₁₀₃₉
13	Val₈₄₁; Lys₈₆₁; Val₉₀₉; Cys₁₀₃₉; Phe₁₀₄₁
14	Asp₈₀₇; Glu₈₇₈; Ile₈₈₁; Leu₁₀₁₃; Cys₁₀₁₈; His₁₀₂₀; Arg₁₀₂₁; Ile₁₀₃₈; Asp₁₀₄₀
15	Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Ile₈₈₁; Leu₈₈₂; Ile₈₈₅; Val₈₉₁; Val₈₉₂; Val₉₀₉; Leu₁₀₁₃; Cys₁₀₁₈; Leu₁₀₂₉; Cys₁₀₃₉; Asp₁₀₄₀
16	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₈₉₂; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
17	Val₈₄₁; Lys₈₆₁; Glu₈₇₈; Leu₈₈₂; Val₈₉₂; Val₉₀₇; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
18	Val₈₄₁; Lys₈₆₁; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
19	Val₈₄₁; Lys₈₆₁; Glu₈₇₈; Val₈₉₂; Val₉₀₉; Cys₁₀₃₉; Phe₁₀₄₁
20	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₈₉₂; Val₉₀₉; Cys₁₀₃₉
21	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₈₉₂; Val₉₀₉; Cys₁₀₃₉
22	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₈₉₂; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
23	Val₈₄₁; Lys₈₆₁; Glu₈₇₈; Val₉₀₉
24	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Val₈₉₂; Val₉₀₉
25	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Val₈₉₂; Val₉₀₉; Cys₁₀₃₉; Phe₁₀₄₁
26	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Val₉₀₉; Leu₁₀₂₉; Cys₁₀₃₉; Phe₁₀₄₁
27	Val₈₄₁; Ala₈₅₉; Lys₈₆₁; Glu₈₇₈; Leu₈₈₂; Val₈₉₂; Val₉₀₉; Cys₁₀₃₉;

Other data indicate that the inhibition constant (Ki) was lower for compounds 1 and 15 compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs (Table 2). It is noteworthy that interaction for compound 1 could be through of hydrophobic bond with Leu₈₈₂ and a polar bond with His₁₀₂ with a 3hng protein surface. In addition, compound 15 could involve coupling via hydrogen bond with Glu₈₇₈, and Asp₁₀₄₀ with 3hng protein surface.

Table 2. Various energies at which carbazole analogs (1-26), decernotinib, and facitinib bind to the 3pjc protein surface.
Compound	A	B	C	D	E	F
Axitinib	-9.60	91.30	-10.00	-0.07	-10.07	886.38
Cabozantinib	-7.70	2.28	-8.77	-0.18	-8.95	1000.65
Pazopanib	-8.76	380.77	-10.15	-0.11	-10.26	999.38
Regorafenib	-5.05	198.17	-6.84	-0.09	-6.93	1004.77
1	-8.18	1.01	-9.13	-0.09	-9.22	832.63
2	-8.86	322.19	-9.76	-0.05	-9.81	778.327
3	-5.43	103.85	-6.76	+0.13	-6.62	601.43
4	-5.29	132.14	-5.78	-0.11	-5.89	452.762
5	-5.29	131.89	-5.91	-0.09	-6.00	618.227
6	-4.41	588.45	-3.42	-1.29	-4.71	324.656
7	-5.39	111.96	-5.65	-0.04	-5.69	442.002
8	-6.25	26.34	-6.72	-0.07	-6.79	506.598
9	-6.66	13.13	-7.14	+0.05	-7.09	577.614
10	-5.45	101.04	-5.46	+0.00	-5.45	328.935
11	-6.51	16.89	-6.54	+0.03	-6.51	420.898
12	-5.27	138.19	-5.56	-0.00	-5.56	378.072
13	-4.73	339.02	4.73	-0.00	-4.73	353.959
14	-6.93	8.30	-7.66	-0.01	-7.67	757.683
15	-7.82	1.85	-9.93	-0.05	-9.98	896.067
16	-4.63	404.38	-5.14	-0.09	-5.23	405.007
17	-6.74	11.50	-6.81	-0.09	-6.90	57.287
18	-4.13	932.21	-4.14	+0.00	-4.13	328.053
19	-4.96	233.30	-5.21	-0.05	-5.25	369.284
20	-5.02	210.70	-5.03	+0.01	-5.02	361.576
21	-5.27	137.86	-5.34	+0.07	-5.27	397.849
22	-5.53	88.52	-5.55	+0.02	-5.53	411.912
23	-4.46	540.62	-4.45	-0.01	-4.46	330.74
24	-5.33	123.09	-5.35	+0.01	-5.33	354.272
25	-5.52	90.67	-5.45	-0.06	-5.52	406.755
26	-5.77	58.74	-5.76	-0.02	-5.77	423.77
27	-6.85	9.52	-6.85	+0.00	-6.85	459.872

A = Est: Free Energy of Binding (kcal/mol); B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

Other data suggest that coupling of bicyclo derivatives (compounds 1-27) with 2oh4 protein displayed differences in amino acid residues involved in 2oh4 protein surface compared with cabozantinib and cediranib drugs (Table 3).

Table 3. Coupling of bicyclic derivatives (1-27), cabozantinib, and cediranib with amino acid residues of 2oh4 protein surface.
Compound	Aminoacid residues
Cabozantinib	Arg₈₄₀; Arg₁₀₄₉; Ile₁₀₅₁; Lys₁₀₅₃; Asp₁₀₅₄
Cediranib	Arg₈₄₀; Lys₈₆₉; Arg₁₀₄₉; Lys₁₀₅₃; Asp₁₀₅₄; Pro₁₀₅₅
1	Arg₈₄₀; Lys₈₆₉; Lys₁₀₅₃; Asp₁₀₅₄; Pro₁₀₅₅
2	Arg₈₄₀; Ala₈₄₂; Lys₈₆₉; Arg₁₀₄₉; Lys₁₀₅₃; Asp₁₀₅₄
3	Arg₈₄₀; Gly₈₄₁; Ala₈₄₂; Lys₈₆₉; Asp₁₀₅₄
4	Arg₁₀₃₀; Arg₁₀₄₉; Asp₁₀₅₀; Ala₁₀₆₃; Pro₁₀₆₆
5	Pro₈₃₇; Arg₈₄₀; Arg₁₀₄₉; Lys₁₀₅₃
6	Asp₁₀₅₄; Pro₁₀₅₅; Asp₁₀₅₆
7	Arg₁₀₃₀; Ala₁₀₄₈; Asp₁₀₅₀; Ile₁₀₅₁; Arg₁₀₆₄; Pro₁₀₆₆
8	Arg₈₄₀; Lys₁₀₅₃
9	Arg₈₄₀; Lys₈₆₉; Arg₁₀₄₉; Lys₁₀₅₃; Asp₁₀₅₄
10	Arg₁₀₃₀; Ala₁₀₄₈; Asp₁₀₅₀; Ile₁₀₅₁; Arg₁₀₆₄; Pro₁₀₆₆
11	Arg₁₀₃₀; Ala₁₀₄₈; Asp₁₀₅₀; Ile₁₀₅₁; Arg₁₀₆₄; Pro₁₀₆₆
12	Phe₈₄₃; Lys₈₆₆; Leu₈₆₈; Ala₈₇₉; Leu₈₈₀; Glu₈₈₃
13	Phe₈₄₃; Lys₈₆₆; Leu₈₆₈; Glu₈₇₆; Ala₈₇₉; Leu₈₈₀
14	Pro₈₃₇; Arg₈₄₀; Arg₁₀₃₀; Arg₁₀₄₉; Asp₁₀₅₀; Lys₁₀₅₃; Asp₁₀₆₂
15	Arg₈₄₀; Ala₈₄₂; Lys₈₆₉; Arg₁₀₄₉; Lys₁₀₅₃
16	Lys₈₆₉; Thr₈₇₃; Glu₈₇₆
17	Ala₈₄₂; Lys₈₆₉
18	Phe₈₄₃; Lys₈₆₆; Leu₈₆₈; Ala₈₇₉; Leu₈₈₀
19	Arg₁₀₃₀; Ala₁₀₄₈; Asp₁₀₅₀; Ile₁₀₅₁; Arg₁₀₆₄; Pro₁₀₆₆
20	Arg₁₀₃₀; Asp₁₀₅₀; Ile₁₀₅₁; Pro₁₀₆₆
21	Arg₁₀₃₀; Ala₁₀₄₈; Asp₁₀₅₀; Ile₁₀₅₁; Arg₁₀₆₄; Pro₁₀₆₆
22	Arg₈₄₀; Lys₈₆₉
23	Phe₈₄₃; Lys₈₆₆; Leu₈₆₈; Glu₈₇₆; Ala₈₇₉; Leu₈₈₀
24	Phe₈₄₃; Lys₈₆₆; Leu₈₆₈; Glu₈₇₆; Ala₈₇₉; Leu₈₈₀; Glu₈₈₃
25	Arg₁₀₃₀; Asp₁₀₅₀; Arg₁₀₆₄; Pro₁₀₆₆
26	Asp₁₀₂₆; Arg₁₀₃₀; Asp₁₀₅₀; Ile₁₀₅₁; Arg₁₀₆₄; Pro₁₀₆₆
27	Arg₁₀₃₀; Ala₁₀₄₈; Asp₁₀₅₀; Ile₁₀₅₁; Pro₁₀₆₆

Furthermore, the Ki was lower for bicyclo derivatives 4, 7, 8, 10, 12, and 15-22 compared with cabozatinib and cediranib drugs (Table 4). This phenomenon, could due to interaction of compounds 4, 7, 8, 10, 12, and 15-22 with some aminoacid residues; for example for compound 4 through hydrogen bond with Arg₁₀₄₉ and hydrophobic bond with Pro₁₀₆₆; for 7 via hydrophobic bond with Ala₁₀₄₈, Ile₁₀₅₁, and Pro₁₀₆₆; for with Arg₈₄₀, and Lys₁₀₅₃; for compound 10 through hydrogen bond with Arg₁₀₆₄ and hydrophobic bond with Ala₁₀₄₈ and Ile₁₀₅₁; for 12 via hydrophobic bond with Phe₈₄₃, Leu₈₆₈, Ala₈₇₉ and Leu₈₈₀; for compound 15 through hydrogen bond with Arg₈₄₀ and hydrophobic bond with Ala₈₄₂; for 16 via polar bound with Glu₈₇₆; for 17 with aminoacid residues such as Ala₈₄₂ and Lys₈₆₉; for 18 through hydrophobic bond with Phe₈₄₃, Leu₈₆₈, Ala₈₇₉ and Leu₈₈₀; for 19 via polar bond Arg₁₀₃₀ and Arg₁₀₆₄ and hydrophobic bond with Ala₁₀₄₈, Ile₁₀₅₁ and Pro₁₀₆₀; for compound 20 through polar bound with Arg₁₀₃₀ and hydrophobic bond with Ile₁₀₅₁ and Pro₁₀₆₆; for 21 via polar bound with Arg₁₀₃₀ and Arg₁₀₆₄and hydrophobic bond with Ala₁₀₄₈, Ile₁₀₅₁ and Pro₁₀₆₆; for compound 22 with Arg₈₄₀and Lys_869.

Table 4. Thermodynamics parameters involved in the interaction of bicyclic derivatives (1-27), cabozantinib, and cediranib with 2oh4 protein surface.
Compound	A	B	C	D	E	F
Cabozantinib	-5.15	168.22	-5.81	-0.18	-5.99	671.90
Cediranib	-4.53	474.23	-4.75	-0.39	-5.14	615.74
1	-4.32	686.33	-5.31	-0.14	-5.44	593.403
2	-4.66	380.73	-5.55	+0.00	-5.55	625.531
3	-4.21	825.61	-5.30	-0.10	-5.40	509.798
4	-3.72	1.88	-4.15	-0.17	-4.32	486.822
5	-4.83	289.72	-5.21	-0.01	-5.23	512.918
6	-4.32	684.73	-2.17	-2.44	-4.62	185.871
7	-3.69	1.96	-3.78	-0.21	-3.99	437.277
8	-3.68	1.99	-4.22	-0.06	-4.27	453.462
9	-4.62	412.93	-5.29	+0.07	-5.22	517.217
10	-4.00	1.17	-3.95	-0.05	-4.00	307.113
11	-4.50	501.37	-4.44	-0.06	-4.50	392.868
12	-3.85	1.52	-4.14	-0.00	-4.14	346.732
13	-4.13	939.89	-4.13	-0.00	-4.13	311.138
14	-6.64	13.48	-7.31	-0.05	-7.36	662.596
15	-3.94	1.29	-6.15	+0.06	-6.08	678.07
16	-3.37	3.37	-3.64	-0.33	-3.97	309.652
17	-3.80	1.64	-3.67	-0.06	-3.73	398.224
18	-3.65	2.10	-3.65	-0.00	-3.65	285.446
19	-3.65	2.11	-3.84	-0.11	-3.95	338.907
20	-3.90	1.39	-3.79	-0.11	-3.90	334.548
21	-4.05	1.08	-3.87	-0.17	-4.05	370.26
22	-3.56	2.44	-3.70	+0.13	-3.56	351.532
23	-4.16	887.31	-4.13	-0.03	-4.16	307.633
24	-4.31	696.25	-4.32	+0.01	-4.31	322.443
25	-4.15	910.75	-3.98	-0.17	-4.15	388.441
26	-3.96	1.26	-4.04	+0.09	-3.96	413.098
27	-4.43	570.49	-4.31	-0.11	-4.43	443.151

A = Est: Free Energy of Binding (kcal/mol); B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

Finally, other data (Table 5) indicate that there are differences in the number of amino acid residues involved in the interaction of bicyclo derivatives 1-27 with 4sbj protein surface compared with axitinib, and cediranib drugs.

Table 5. Coupling of bicyclic derivatives (1-27), axitinib, and cediranib with amino acid residues of 4sbj protein surface.
Compound	Aminoacid residues
Axitinib	Ala₄₀₀; Leu₄₀₁; Trp₄₀₂; Arg₄₀₉; Arg₄₁₀; Asn₄₁₁
Cediranib	Tyr₃₆₉; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
1	Tyr₃₆₉; Thr₃₉₈; Ala₄₀₀; Trp₄₀₂; Ser₄₀₄; Arg₄₀₉; Asn₄₁₁
2	Tyr₃₆₉; Thr₃₉₈; Ala₄₀₀;, Arg₄₀₉; Asn₄₁₁
3	Tyr₃₆₉; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
4	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
5	Tyr₃₆₉; Ala₄₀₀;Leu₄₀₁; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
6	Ala₄₀₀;Leu₄₀₁; Trp₄₀₂; Arg₄₀₉; Arg₄₁₀; Asn₄₁₁
7	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
8	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
9	Tyr₃₆₉; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
10	Tyr₃₆₉; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
11	Tyr₃₆₉; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
12	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
13	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
14	Tyr₃₆₉; Thr₃₉₈; Ala₄₀₀; Trp₄₀₂; Asn₄₁₁
15	Tyr₃₆₉; Thr₃₉₈; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
16	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
17	Tyr₃₆₉; Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
18	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
19	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
20	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
21	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
22	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
23	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
24	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
25	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
26	Ala₄₀₀; Trp₄₀₂; Arg₄₀₉; Asn₄₁₁
27	Trp₄₀₂; Arg₄₀₉; Asn₄₁₁

Besides, the Ki for bicyclo derivatives of compounds 4, 6-8, 10, 12, 13, 16, 18-21, 23, 24, and 26 was lower compared with axitinib and cediranib drugs. This results could be to coupling of different aminoacid residues involved in each protein surface; for example for bicyclo derivative 4 (Table 6) through polar bound with Arg₄₀₉₀ and Asn₄₁₁; hydrophobic bond with Ala₄₀₀and Trp₄₀₂; for 6 via hydrogen bond Leu₄₀₁, Arg₄₁₀ and Asn₄₁₁ and hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 7 through polar bond Arg₄₀₉ and hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 8 via hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for compound 10 through hydrophobic bound with Ala₄₀₀ and Trp₄₀₂ and halogen-bond Tyr₃₆₉; for 12 via hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 13 through hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 16 via polar bond Arg₄₀₉ and Asn₄₁₁ and hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for compound 18 through hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 19 via polar bound with Asn₄₁₁ and hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 20 through hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 21 via polar bound with Arg₄₀₉and hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 23 through hydrophobic bond with Ala₄₀₀ and pi-pi bound with Trp₄₀₂; for 24 via hydrophobic bond with Ala₄₀₀ and Trp₄₀₂; for 26 through hydrophobic bond with Ala₄₀₀ and Trp₄₀₂.

Table 6. Thermodynamics parameters involved in the interaction of bicyclic derivatives (1-27), axitinib, and cediranib with 4bsj protein surface.
Compound	A	B	C	D	E	F
Axitinib	-6.96	7.87	-7.74	0.00	-7.74	629.46
Cediranib	-4.92	248.37	-4.71	0.11	-4.60	475.52
1	-4.83	288.81	-6.05	+0.02	-6.03	642.309
2	-4.75	327.53	-5.53	-0.01	-5.54	571.586
3	-4.26	756.37	-5.41	-0.04	-5.45	468.482
4	-3.27	4.04	-3.77	-0.09	-3.86	364.033
5	-4.70	358.24	-5.47	-0.00	-5.47	461.545
6	-3.32	3.71	-3.52	-0.10	-3.61	265.362
7	-3.93	1.32	-4.04	-0.18	-4.22	361.663
8	-3.87	1.47	-4.43	+0.03	-4.41	407.43
9	-4.65	392.57	-4.94	-0.07	-5.02	429.595
10	-3.97	1.24	-3.95	-0.02	-3.97	266.541
11	-4.48	520.45	-4.46	-0.01	-4.48	345.514
12	-3.92	1.35	-4.21	-0.00	-4.21	311.676
13	-3.87	1.46	-3.87	-0.00	-3.87	289.115
14	-4.44	555.92	-5.15	-0.00	-5.15	545.316
15	-4.21	826.34	-6.10	+0.02	-6.08	659.82
16	-3.23	4.30	-3.79	-0.04	-3.83	324.767
17	-4.73	343.36	-4.66	-0.02	-4.68	381.591
18	-3.56	2.44	-3.56	-0.01	-3.56	263.194
19	-3.84	1.53	-4.11	-0.03	-4.14	299.916
20	-3.99	1.18	-4.00	+0.00	-3.99	289.691
21	-4.02	1.14	-3.95	-0.07	-4.02	328.993
22	-4.25	766.59	-4.17	-0.08	-4.25	345.759
23	-3.50	2.71	-3.51	+0.01	-3.50	278.369
24	-4.05	1.08	-4.04	-0.01	-4.05	292.545
25	-4.18	863.98	-4.11	-0.07	-4.18	338.722
26	-4.04	1.10	-3.97	-0.07	-4.04	333.875
27	-4.45	545.67	-4.43	-0.02	-4.45	365.436

A = Est: Free Energy of Binding (kcal/mol); B = Est. Inhibition Constant, Ki (mM)

C = vdW + Hbond + desolv Energy (kcal/mol); D = Electrostatic Energy (kcal/mol)

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

Conclusion

This research has reported the interaction of bicyclo analogs to the VEGR-1, VEGR-2, AND VEGR-3 surface using 3hng, 2oh4, and 4bsj proteins as theoretical tools. The results indicated the following; i) bicyclo derivatives 1 and 15 could have a higher affinity for 3hng protein surface compared with axinib, cabozatinib, cediranib, pazonib, and regorafenib drugs; ii) Besides, the Ki for coupling of 4, 7, 8, 10, 12, and 15-22 with 2oh4 protein surface was lower compared with cabozatinib and cediranib drugs. Finally, the results for the interaction of bicyclo analogs 4, 6-8, 10, 12, 13, 16, 18-21, 23, 24, and 26 were lower compared with axitinib and cediranib drugs. All these data suggest that bicyclo derivatives 1, 4, 6-8, 10, 12, 13, 15-24, and 26 could modulate the biological activity produced by VEGR-1, VEGR-2, and VEGR-3; this phenomenon could translated as good anticancer agents.

Acknowledgments

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Cite this article

Vancouver

Lopez-Ramos M, Figueroa-Valverde L, Rosas-Nexticapa M, Alvarez-Ramirez M, Mateu-Armand V, Cauich-Carrillo R. Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer. Clin Cancer Investig J. 2024;13(5):1-9. https://doi.org/10.51847/tFgoN65qlJ

APA

Lopez-Ramos, M., Figueroa-Valverde, L., Rosas-Nexticapa, M., Alvarez-Ramirez, M., Mateu-Armand, V., & Cauich-Carrillo, R. (2024). Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer. Clinical Cancer Investigation Journal, 13(5), 1-9. https://doi.org/10.51847/tFgoN65qlJ

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Interaction of Twenty-Seven Bicyclo Derivatives with VEGF Receptors as a Therapeutic Alternative to Treat Cancer

Introduction

Materials and Methods

Ligand-protein complex

Results and Discussion

Table 1. Interaction of bicyclic derivatives (1-27), axitinib, cabozantinib, pazopanib, and regorafenib with amino acid residues of 3hng protein surface.

Table 2. Various energies at which carbazole analogs (1-26), decernotinib, and facitinib bind to the 3pjc protein surface.

Other data suggest that coupling of bicyclo derivatives (compounds 1-27) with 2oh4 protein displayed differences in amino acid residues involved in 2oh4 protein surface compared with cabozantinib and cediranib drugs (Table 3).

Table 3. Coupling of bicyclic derivatives (1-27), cabozantinib, and cediranib with amino acid residues of 2oh4 protein surface.

Table 4. Thermodynamics parameters involved in the interaction of bicyclic derivatives (1-27), cabozantinib, and cediranib with 2oh4 protein surface.

E = Total Intermolec. Energy (kcal/mol); F = Interact. Surface.

Finally, other data (Table 5) indicate that there are differences in the number of amino acid residues involved in the interaction of bicyclo derivatives 1-27 with 4sbj protein surface compared with axitinib, and cediranib drugs.

Table 5. Coupling of bicyclic derivatives (1-27), axitinib, and cediranib with amino acid residues of 4sbj protein surface.

Table 6. Thermodynamics parameters involved in the interaction of bicyclic derivatives (1-27), axitinib, and cediranib with 4bsj protein surface.

Conclusion

Acknowledgments

Conflict of interest

Financial support

Ethics statement