Interaction of benzenesulfonamide derivatives with Smyd3 using a theoretical model

Cancer is a serious public health problem worldwide. This clinical pathology is associated with the activation/release of several biomolecules, including the Smyd proteins family. In this way, some studies indicate that Smyd3 is associated with cancer cells growth. It is important to mention that some drugs act as Smyd3 inhibitors in the treat some cancers. However, their interaction is very confusing; for this reason, the aim of this research was to evaluate the theoretical interaction of benzenesulfonamide and their derivatives (compounds 2 to 28 ) using 7o2c protein, novobiocin, BAY-6035, EPZ031686 and BCI-121 drugs as theoretical tools in DockingServer program. The results showed differences in the aminoacid residues involved in the interaction of benzenesulfonamide and their derivatives with 7o2c protein surface compared with novobiocin, BAY-6035, EPZ031686 and BCI-121 drugs. In additions, the inhibition constant (Ki) for benzenesulfonamide derivatives 2, 7, 8, 13, 14, 17, 20, 21, 24 and 28 was very lower compared to benzenesulfonamide, novobiocin, BAY-6035, EPZ031686 and BCI-121. In conclusion, the benzenesulfonamide derivatives 2, 7, 8, 13, 14, 17, 20, 21, 24 and 28 could be a good alternative as Smyd3 inhibitors to decrease cancer cells growth.

In this way, there are studies have shown that Smyd3 may be associated to some regulatory pathways in cancer cells growth (Giakountis et al., 2017); for example, a study showed that Smyd3 can promotes cell cycle progression by inducing cyclin D3 transcription and stabilizing the cyclin D1 protein in medulloblastoma (Asuthkar et al., 2022).Other data indicate that Smyd3 may associate with the NuRD (Nucleosome Remodeling Deacetylase) to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells (Yang et al., 2022).
Besides, a report-displayed that Smyd3 promotes aerobic glycolysis in diffuse B-cell lymphoma via H3K4me3 (histone trimethylated at lysine 4 which is associated with active chromatin and gene expression) mediated PKM2 (pyruvate kinase) transcription (Tian et al., 2022).Another report shows that Smyd3 may promotes oral squamous cell carcinoma tumorigenesis via H3K4me3-mediated HMGA2 (High-mobility group AT-hook 2) transcription (Yang et al., 2023).In addition, a study indicate that Smyd3 may promotes TGFβ (transforming growth factor-β) dependent mesenchymal gene expression and cell migration in breast cancer (Fenizia et al., 2019).
On the other hand, to decrease the biological activity produced by Smyd3 in cancer cells have been used some drugs; for example, a study showed that compound BCI-121 (4-(aminocarbonyl)-N-(4-bromophenyl)-1-piperidineacetamide) significantly decreased the biological activity of Smyd3, resulting in decreased colorectal cancer cells growth (Peserico et al., 2015).Besides, a report indicate that novobiocin decreases Smyd3 expression and inhibits the migration of MDA-MB-231 human breast cancer cells (Luo et al., 2010).Other report showed that BAY-6035 act as Smyd3 inhibitor using high-throughput detection based on a heat exchange assay (Gradl et al., 2021).Besides, a study showed that compound EPZ031686 inhibith the biological activity of Smyd3 using a pharmacokinetic model (Mitchell et al., 2016).
All these data suggest that some drugs can act as Smyd3 inhibitors; however, the interaction of these compounds with Smyd3 surface is not clear.Analyzing these data, the aim of this research was to evaluate the possible interaction of benzenesulfonamide and their derivatives with Smyd3 using 7o2c protein, novobiocin, BAY-6035, EPZ031686 and BCI-121 drugs (Figure 1) as theoretical tools in DockingServer program (Figueroa-Valverde et al., 2021).

Electronic parameters
The frontier molecular HOMO, LUMO were calculated using the Spartam´86 program (Spillane et al., 2003).

Electronic parameters
In the Table 1 and Figure 3 nd 4 are showed some physicochemical parameters of benzenesulfonamide (1) and their derivatives (2-28).

Ligand-protein complex
Table 2 shows the different aminoacid residues involved in the interaction of benzenesulfonamide and its derivatives (compounds 2-28) with 7o2c protein surface.Other data suggest that some aminoacid residues of 7o2c protein surface can interact with novobiocin, BAY-6035, EPZ031686 and BCI-121 drugs.

Toxicology analysis
The results of theorethical evaluation of toxicity for bencenesulfonamide derivatives (2, 7, 8, 13, 14, 17, 20, 21, 24 and 28) are showed in the Table 5.These data indicate that toxicity could depend of dose administered for bencenesulfonamide derivatives through of different routes of administration.

Discussion
There are several studies which indicate that some Smy3 inhibitors can be used to try slow cancer cells growth (Mitchell et al., 2016;Gradl et al., 2021); however, the interaction of these compounds with Smy3 is not clear.For this reason, a theoretical study was conducted to evaluate the possibility that benzenesulfamide and their derivatives could interact with Smy3 surface as follows: 4.1 Electronic parameters.
Some data indicate that frontier electron density can been used for predicting the most reactive position in π-electron systems and several types of reactions in conjugated system.It is important to mention that highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) values and their energy gap can reflect the chemical activity of a molecule (Prasad et al., 2008).In this way, some methods such as density functional teory (matunova et al., 2019), Multiwfn software (Manoj et al., 2022) and Gaussian software (Rijal et al., 2022) have been used to evaluate frontier molecular orbitals (HOMO-LUMO gap) of some compounds (Srivastava et al., 2005;Ferro et al., 2006).
In the literature, there are some computer modeling such as DOCK (Mosquera-yuqui et al., 2022), GROMAS (Qu et al., 2022), SFs (Shen et al., 2020), Swarm Dock (Torchata et al., 2020 to evaluate the formation of the ligand-protein complex.The aim of this research was to evaluate the interaction of benznesulfonamide and their derivatives (compounds 1 to 28) with the Smyd3 protein surface using the 7o2c protein, novobiocin, BAY-6035, BCI-121 and EPZ031686 as theoretical tools in DockingServer software.

Bond energies evaluation
Several reports have showed that protein-ligand complex formation could depend of several thermodynamic parameters (Figueroa-Valverde et al., 2023).For this reason, in this study some thermodynamic factors such as free energy of binding, inhibition constant, Van der Waals + hidrogen bond + desolv energy (vdW + Hbond + desolv Energy), electrostatic energy and total intermolecular energy were determined using the DockingServer model.The results shows differences in energies values for benzenesulfonamide (1) and their derivatives (2-28), novobiocin, BAY-6035, BCI-121 and EPZ031686.

Pharmacokinetic evaluation.
In the literature, there are some methods to predict different pharmacokinetic processes involved in the administration of several drugs such as Phoenix WinNonlin (Zhao et al., 2022), PKMP (Shah, 2022), CertaraPhonix (Li et al., 2020) andSwissADME (Mekki et al., 2022).For this reason, in this research, some pharmacokinetic factors for benzenesulfamide derivatives (2, 7, 8, 13, 14, 17, 20, 21, 24 and 28) were evaluated using SwissADME software.The results suggest differences in gastrointestinal absorption and metabolism, which involve several cytochrome P450 systems.This phenomenon could be to differences in the chemical structure of each benzenesulfonamide derivative and their degree of lipophilicity (LogPO/W).

Conclusions
This research reports the interaction of benzenesulfonamide and their derivatives with Smyd3.The results showed that the benzenesulfonamide derivatives 2, 7,8,13,14,17,20,21,24 and 28 could be a good alternative as Smyd3inhibitors and this phenomenon could translate into a decrease in cancer cell growth.However, it is worth mentioning that experimental data is required to support this hypothesis.

Authors' Contributions
Substantial contribution to research design: Figueroa-Valverde Lauro and Diaz-Cedillo Francisco; Acquisition, analysis and interpretation of data: Figueroa-Valverde Lauro L, Diaz-Cedillo Francisco, Alvarez-Ramirez Magdalena, Rosas-Nexticapa Marcela, Lopez-Ramos Maria and Mateu-Armand Virginia.Approval of the submitted and final versions: all authors.

Funding
This research received no external funding.

Conflict of interest
The authors declare that this research has no conflict of interest with any public or private association.

Table 1 .
Physicochemical parameters for benzenesulfonamide (1) and their derivatives (2-28) involved in the chemical structure.The values were calculated using Spartan software.

Table 5 .
Theoretical toxicity analysis produced by bencenesulfonamide derivatives.