Evaluation of coumarin and their derivatives as Janus Kinase-3 inhibitors using a theoretical model

For several years, cancer has increased in the population, being one of the main causes of death worldwide. This clinical pathology is associated with the activation/release of various biomolecules, including the Janus kinase family (JAKs). It is important to mention that some studies indicate that some JAK inhibitors (ruxolitinib and tofacitinib) may have a significant effect on some autoimmune diseases and cancer; however, some of these drugs can produce secondary effects such as herpes zoster, infectious, acute respiratory distress and others. The aim of this study was to evaluate the interaction of coumarin and its derivatives (compounds 2 to 24) with the JAK-3 surface. In this way, the Interaction of coumarin and their derivatives with JAK-3 was determined using the 3pjc protein and either decernotinib or tofacitinib drugs as theoretical tools on DockinServer program. The results showed differences in the aminoacid residues involved in the interaction of coumarin and their derivatives with 3pjc protein surface compared with decernotinib and tofacitinib. Besides, the inhibition constant (Ki) for coumarin derivatives 7, 9 and 10 was lower compared with tofacitinib. However, Ki was lower for 2, 5, 7, 8, 9, 10, and 24 compared with decernotinib. In conclusion, the coumarin derivatives 2, 5, 7, 8, 9, 10, and 24 could be good alternatives as JAK-3 inhibitors to decrease cancer cells growth.

Besides, there are some data indicating that some genetic factors may involving in cancer cells growth (De-Magalhães, 2022); for example, a study showed some mutations in KRAS gene (Kirten rat sarcoma viral) which were associated with colorectal cancer (Hayama et al., 2019). Other report indicate that BCR-ABL (transcript encodes a tyrosine kinase) gene mutations are associated with different forms of leukaemia (Zhang et al., 2016). In addition, some studies suggest that either androgen receptor or 5α-reductase enzyme are two factors associated to prostate cancer (Sowalsky et al., 2022;Lopez-Ramos et al., 2023).
Other data showed that HER2 (human epidermal growth factor receptor 2) overexpression could condition tumor growth in patients with breast cancer (Asgari-Karchekani et al., 2022;Grupta et al., 2022). Besides, some studies indicate that MYC (family of regulator genes and proto-oncogenes that code for transcription factors) may contribute to the progression of various human cancers (Dhanasekaran et al., 2022;Ala, 2022). Other study shows that EGFR (Epidermal growth factor receptor) gene is mutated and overactive in many cancers, including lung, breast, esophageal, head, and neck cancers (Seshacharyulu et al., 2012;Sigismund et al., 2018).
On the other hand, there are some studies suggesting that Activation of JAKs (Janus kinase family; JAK-1, JAK-2 and JAK-3) is involved in cancer cells growth (Verma et al., 2003). For example, a study showed that The JAK3/ERK (Janus kinase-3/extra-cellular signal-regulated kinase) pathway might play an important role in EGFR-induced MMP-9 (matrix metallopeptidase 9) expression in breast cancer cells (Kim et al., 2009). Other study conducted in 932 clinical cases of non-small cell lung cancers (NSCLC) showed mutations in JAK2 and JAK3 using the Ion AmpliSeq Cancer Hotspot panel v2 assay (Li et al., 2017).
Besides, cell invasion of highly metastatic MTLn3 (a highly metastatic rat mammary adenocarcinoma cell line) cancer cells which is dependent of both phospholipase D2 (PLD2) and JAK-3 (Henkels et al., 2011). Another report suggests that JAK 3 may have a cytokine receptor-independent function; however, JAK-3 levels can increase in cutaneous T-cell lymphoma (Vadivel et al., 2021). All these data indicate that JAK-3 can produce changes in cancer cells growth. Here it is important to mention that some JAKs inhibitors have been used for treat some cancer cell lines; for example, a study showed that ruxolitinib (JAK1/2 inhibitor) synergistically enhances the anti-tumor activity of paclitaxel in human ovarian cancer (Han et al., 2018).

Ligand-protein complex
In the table 1 showing different aminoacid residues involved in the coupling of coumarin and their derivatives (compounds 2-24) with 3pj protein surface.

Thermodynamic parameters
The theoretical results indicate differences in the energy levels involved in the interaction of coumarin and its derivatives with JAK-3 (3pjc protein) compared with both decernotinib and tofacitinib drugs (Table 2).  Table 3 shows that gastrointestinal (GI) absorption rate was high for either decernotinib or facitinib drugs and the coumarin derivatives 2, 5, 7, 8-10 and 24. In addition, The CYPs involved in the pharmacokinetic process were different. Note: GI = Gastrointestinal; BBB = Blood-Brain-Barrier; P-gp = P-glycoprotein; CYP = Cytochrome P450; LogPO/W = Octanol-water partition coefficient. Source: Authors, 2023. Table 4 showed differences in the possible dose administered for either decernotinib or tofacitinib drugs and the coumarin derivatives 2, 5, 7, 8-10 and 24 through the different routes of administration.

Discussion
In the literature there are some studies indicating that JAK-3 may be associated with cancer cells growth (Verma et al., 2003;Kim et al., 2009;Li et al., 2017;Henkels et al., 2011;Vadivedel et al., 2021). For this reason, a theoretical study was conducted in this investigation to evaluate the possibility that coumarin and their derivatives could interact with JAK-3 surface using the DockingServer software.

Ligand-protein analysis.
Computer modeling has been developed and widely applied in studying molecules to evaluate their possible biological activity (Crampon et al., 2022;Ota et al., 2022;. Analyzing this data, the interaction of coumarin and their derivatives (compounds 2 to 24) with the JAK-3 surface was determined using the 3pjc protein (crystal Structure of JAK-3) as control. In addition, some JAK-3 inhibitors such as decernotinib and tofacitinib served as theoretical tools on DockingServer software. The results display different amino acid residues involved in the interaction of coumarin and their derivatives with 3pjc protein surface compared with decernotinib and tofacitinib; this phenomenon could be due to differences in their chemical structure.

Bond energies analysis
There are some studies which suggest that protein-ligand complex formation could depend of several 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 (Figueroa-Valverde et al., 2021). For this reason, in this research some thermodynamic parameters involved in the interaction of coumarin and its derivatives with the 3pjc surface protein were evaluated using the DockingServer model. The results ( Table 2) showed differences in the energies levels for coumarin and their derivatives compared with decernotinib and tofacitinib.
Besides, inhibition constant (Ki) for coumarin derivatives 7, 9 and 10 was lower compared with tofacitinib. However, Ki was lower for 2, 5, 7, 8, 9, 10 and 24 compared with decernotinib. These data indicate that coumarin derivatives 2, 5, 7, 8, 9, 10 and 24 could inhibit the biological activity of JAK-3 and this phenomenon could be translated as decrease in cancer cells growth. However, it is important to mention that some pharmacokinetic parameters involved in the chemical structure of coumarin derivatives need to be evaluated in some cancer model.

Pharmacokinetic evaluation.
In the literature, some methods to predict several pharmacokinetic parameters of different drugs have been used to determinate their biological activity (Nguyen et al., 2022;Valluri et al., 2022;Goutelle et al., 2022). For this reason, in this research, some pharmacokinetic factors for coumarin derivatives such as 2, 5, 7, 8, 9, 10 and 24 were determined using SwissADME software (Table 3).
The results indicate differences in gastrointestinal absorption and metabolism which involving several cytochrome P450 systems. This phenomenon could be to differences in the chemical structure of each coumarin derivatives and their degree of lipophilicity (LogPO/W).
The results shown in Table 4 suggest that tofacitinib require low doses via either intravenous or intraperitoneal or subcutaneous routes to produce toxicity compared to coumarin derivatives. Besides, decernotinib require higher dose to produce toxicity compared with coumarin derivatives 2, 5, 7 and 8-10; however, compound 24 require higher dose to produce toxicity compared with decernotinib. These results could be due to differences in their lipophilicity degree of each coumarin.

Conclusions
This study reports the interaction of coumarin derivatives, decernotinib and tofacitinib with JAK-3. The results showed that the coumarin derivatives 2, 5, 7, 8, 9, 10 and 24 could be a good alternative as JAK-3 inhibitors and this phenomenon could translate into a decrease in cancer cell growth.

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.

Ethics Approval
Not applicable.