thiophene-triazine derivative decreased the growth of MCF-7 cancer cells through PI3K/mTOR (phosphoinositide 3-kinase/mammalian target of rapamycin) pathway inhibition.^[25] All these experimental data indicate that some thiophene derivatives can inhibit breast cancer growth; nevertheless, its coupling with some biomolecules involved in cell growth in breast cancer patients is unclear. Therefore, this study aimed to determine the possible interaction of several thiophene (compound 1) and their analogs (2 to 25) with BRCA-1 (breast cancer gene 1) using a theoretical model.

Materials and Methods

Figure 1 shows the chemical structure of thiophene and its analogs which were used to determine its possible interaction with the BRCA-1 gene surface as follows:

Figure 1. Chemical structure of thiophene (1) and its derivatives (2-25). 1 = Thiophene 2 = 1-Benzothiophene-4-ol 3 = 1-Methylbenzo(b)naphtho(1,2-d)-thiophene 4= 2-([(E)-(3,5-Dichloro-2-hydroxyphenyl)methylidene]amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile 5 = 2-(1H-Imidazol-1-ylmethyl)-4,5-dihydrobenzo(b)thiophene-6-carboxylic acid 6 = 2-(Chloromethyl)-thiophene 7 = 2-(tert-butoxy)thiophene 8 = 2,2,3-Trifluoro-2,4,5,6,7,8-hexahydrocyclohepta(b)thiophene 9 = 2,5-Dimethyltetrahydrothiophene 10 = 3-(2-(Dimethylamino)ethyl)-5-methoxybenzo(b)thiophene 11 = 3-(2-(Dimethylamino)ethyl)benzo(b)thiophene 12 = 3-(2-(Methylamino)ethyl)benzo(b)thiophene 13 = 3-(2-Aminoethyl)-5-methoxybenzo(b)thiophene 14 = 3-Formylthiophene 15 = 3-Methylbenzo(b)naphtho(1,2-d)thiophene 16 = 3-Nitrobenzo(b)thiophene 17 = 4-Methylbenzo(b)naphtho(2,3-d)thiophene 18 = 5-Bromo-2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-thiophene 19 = 6-Methylbenzo(b)naphtho(2,1-d)thiophene 20 = 6-Methylbenzo(b)thiophene 21 = -Benzothiophene 1,1-dioxide 22 = Tetrahydro-thiophene-1-oxide 23= N-[[4-[(thiophene-2-carbonylamino)carbamoyl]cyclohexyl]methyl]thiophene-2-sulfonamide 24 = Naphtho(2,1-b)thiophene 25= 19-thiapentacyclo[14.2.1.05,18.06,11.012,17]nonadeca-1,3,5(18), 6,8,10, 12(17),13,15-nonaene

Ligand-protein complex

Coupling of thiophene and its derivatives with BRCA-1 was evaluated using 3pxb^[26] protein and niraparib (MK-4827) as theoretical tools in DockingServer software.^[27]

Pharmacokinetics parameter

Some pharmacokinetic parameters for thiophene derivatives (11, 13, 16, 18, and 20) were evaluated using the SwissADME software.^[28]

Toxicity analysis

Possible toxicity induced through different administration routes of thiophene derivatives (11, 13, 16, 18, and 20) and niraparib was evaluated using the GUSAR program.^[29]

Results and Discussion

Some reports indicate that several thiophene derivatives can exert biological activity against cancer cells;^[21-25] nevertheless, experimental results are very confusing. Analyzing these data, this study aimed to evaluate the possible interaction of some thiophene and its derivatives with some biomolecules involved in cancer cell growth such as BRCA-1 using 3pxb protein and niraparib as theoretical tools in a Docking model. The results (Table 1 and Figure 2) showed that LJH685 interacts with different amino acid residues (Leu₁₆₇₉; Ile₁₆₈₀; Arg₁₆₉₉; Ala₁₇₀₀; Leu₁₇₀₁; Lys₁₇₀₂; Leu₁₇₀₅; Gln₁₇₇₉) involved in the 3pxb protein surface in comparison with thiophene (1) and its derivatives (2 to 25). This data indicates that the coupling of thiophene and its analogs with the 3pxb protein surface can depend on the chemical characteristic of each compound (Table 1 and Figure 2) or different thermodynamics parameters involved in the thiophene-protein complex formation. 

Thermodynamic parameters

There are theoretical studies that suggest that coupling of some drugs with several biomolecules may depend on different thermodynamic parameters, such as binding free energy, electrostatic energy, total intermolecular energy, Van Der Waals (vdW) + hydrogen bond (H bond) + desolvation energy.^[29] For this reason, the study of these thermodynamic parameters involved in the interaction of thiophene and its analogs with the 3pxb protein surface was determined. The results (Table 2) displayed different energy levels for thiophene, and its analogs in comparison with niraparib. Furthermore, the inhibition constant (Ki) was higher for thiophene and its analogs 2-10, 12, 14, 15, 17, 19, and 21-25 compared to niraparib. However, Ki for thiophene analogs 11, 13, 16, 18, and 20 was very similar to the niraparib drug. These data suggest that thiophene derivatives 11, 13, 16, 18, and 20 could act as BRCA-1 inhibitory agents. However, it is important to mention that other types of biological experiments are required to verify this hypothesis.

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

Pharmacokinetic evaluation

Several methods have been used to determine some pharmacokinetic parameters to evaluate the possible biological activity of different drugs.^[30-33] For this reason, this research aimed to determine some pharmacokinetic parameters that could be involved in the administration of thiophene analogs 11, 13, 16, 18, 20, and nirapib using the SwissADME program (Table 3). The results showed differences in gastrointestinal absorption degree and metabolism (which involves various types of cytochromes P450 enzymes) for thiophene 11, 13, 16, 18, and 20 compared to the niraparib drug. Possibly this process could be associated with the different chemical characteristics of each thiophene analog and differences in its lipophilicity degree.

Toxicity analysis

Some reports suggest that different thiophene derivatives may produce some toxicity degree using several biological models.^[34-37] This research aimed to evaluate the possible toxicity produced by thiophene analogs (11, 13, 16, 18, and 20) using the GUSAR software.^[28] The results suggest (Table 4) that thiophene derivative 18 possibly requires high doses to produce toxicity (LD50) via intraperitoneal, intravenous, oral, and subcutaneous compared to the niraparib drug. Besides, compound 16 requires a higher dose through the oral route compared to niraparib. All these data indicate that the toxicity degree would depend on the dose and administration route of each thiophene analog.

IP - Intraperitoneal route of administration

IV - Intravenous route of administration

Oral - Oral route of administration

SC - Subcutaneous route of administration

Conclusion

In this study, the possible coupling of thiophene and its analogs with the 3pxb protein surface. The results indicate that thiophene derivatives 11, 13, 16, 18, and 20 may interact with some amino acid residues involved in the 3pxb protein surface. This data suggests that thiophene derivatives 11, 13, 16, 18, and 20 could act as BRCA-1 gene inhibitor agents; this phenomenon could be translated as a decrease in breast cancer cell growth. Analyzing these data these thiophene derivatives may be considered good pharmacological agents to treat breast cancer.

Acknowledgments

None.

Conflict of interest

None.

Financial support

None.

Ethics statement

All procedures in this study were performed in accordance with protocols for Pharmacochemistry Laboratory of University Autonomous of Campeche.

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