Over the past few decades, research efforts have successfully contributed to identify potential anti-diabetic agents having FDA approval for clinical use. A dataset comprising clinically approved anti-diabetic agents was constructed, and the details of chemical structures, mechanism of action, pharmacokinetic profile, and side effects have been collected.
In human cancer cells, the hERG is often overexpressed on their plasma membrane and regulates proliferation, survival, migration/invasiveness, and neoangiogenesis. Thus, selective inhibitors of hERG can be used as anticancer therapeutics [24, 25]. A similar role of hERG on glioblastoma has been reported by Pointer and colleagues and suggests the application of similar strategies to control other types of cancers. The publicly available PredhERG application was used to predict blockers and non-blockers of the hERG channels from the constructed dataset of anti-diabetic agents. The binary and multi-classification models could significantly classify blockers and non-blockers of hERG which is an important drug anti-target associated with lethal cardiac arrhythmia.
The molecular docking study was performed using the reported molecular structure of hERGT and hERGTS (3.8 Å) (PDB IDs: 5VA2 and 5VA1, respectively) [Wanfg et al., 2017]. The study reports depolarized conformation (open and voltage sensors) of the channel and presence of a unique central cavity which contributes to hERG block by many drugs. The pockets are not present in other K+ channels, and the small volume favors the stable binding of cationic drugs and amplifies the electrostatic potential. The asymmetric binding of drugs causes partial occupancy of the functional groups in the hydrophobic pockets.
The docking study of the selected set of compounds displayed the best binding pose of the respective compounds within the active sites of 5VA1 and 5VA3, elucidated the interactions involved in the binding of the compounds with the receptors and showed the effect of the mutation on the affinity of the compounds to the target receptor (Table 2).
The putative drug-binding site of 5VA1 includes the following residues: THR623, SER624, and VAL625 on the pore helix and residues GLY648, TYR652, and PHE656, located on segment S. Bromocriptine and Darglitazone occupied the active site of the receptor and interacted with the active site’s residues through hydrogen bond and hydrophobic interactions. For Bromocriptine, the hydrogen bond formed between the oxygen atom of the ligand and the residue THR623 (Fig. 2) while the amino group of Darglitazone was involved in a hydrogen bond with THR623 (Fig 3). Both ligands formed hydrophobic interactions with the residues MET554, PHE619, and VAL625. Additionally, the phenyl group of Darglitazone displayed aromatic interaction with the aromatic amino acid PHE656.
The second selected receptor 5VA3 is the mutated type of hERG channel in which the residue SER631 was replaced with ALA631. The binding mode of Bromocriptine and Balaglitazone within the active site of 5VA3 was like their binding mode within the active site of 5VA1. Both the compounds showed interactions with 5VA3 similar to that with 5VA1. The two compounds formed hydrogen bonds with THR623 and formed hydrophobic interactions with MET554, PHE619, and VAL625 in addition to PHE557 and PHE656 (Fig. 4). The phenyl group of Darglitazone displayed aromatic interaction with the aromatic amino acid PHE619 (Fig. 5).
Although Bromocriptine and Darglitazone exhibited low binding energies to 5VA3, these two compounds did not show the highest affinity for 5VA3. As can be seen in Table 2, Troglitazone showed the lowest binding energy to 5VA3 (−7.5 Kcal/mol) amongst all the 26 compounds. Therefore, this compound has the highest affinity for the target receptor. Troglitazone is involved in two hydrogen bonds with the residues THR613 and THR623. These hydrogen bonds formed between the two oxygen atoms of the ligand and THR613 and THR623, respectively (Fig. 6). The oxygen atoms acted as hydrogen bond acceptors. Moreover, the ligand was also involved in hydrophobic interactions with LEU589, ILE593, ASP609, VAL612, TYR616, and VAL630.
The docking study has shown the main amino acids that are essential for the binding of the ligand to the target receptors. These amino acids are THR623 and VAL625. Besides, it has been shown that replacing SER631 with LAL631 did not affect the binding affinity of most of the compounds except Troglitazone which showed a higher affinity to the mutated protein than the wild type.
When the derived results were compared with the previously reported data, we found anti-cancer potential of some of the selected compounds. Cytotoxic potential of the selected four hERG blockers namely, Bromocriptine, Balaglitazone, Darglitazone, and Troglitazone have been reported through in vitro/in vivo experimental methods in various cancer types. Bromocriptine, a sympatholytic, D2-dopamine agonist used for the treatment of type 2 diabetes [26] has been investigated for the treatment of metastatic breast cancer, prostate cancer-related hyperprolactinemia [27]. Bromocriptine has a cytotoxic profile towards drug-sensitive CCRF-CEM, multidrug-resistant (MDR) CEM/ADR5000 leukemic cells, and MDR ABCB5-transfected HEK293 cell lines. The proposed mechanism for cytotoxicity includes binding to NF-KB proteins [28]. The next antidiabetic agent Balaglitazone, a second-generation peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, could reverse P-glycoprotein-mediated MDR by upregulating phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in leukemia cells [29]. The PPAR-γ agonists (Troglitazone) have been investigated as a combination with other drugs such as lovastatin in human anaplastic thyroid cancer cell line and in a mouse xenograft model [30]. Troglitazone in combination with aspirin has shown cell cycle arrest and apoptosis in human lung cancer cells [31]. In a recent study, Troglitazone has significantly suppressed the growth of human oral SCC cells but failed to induce apoptosis [32]. In pancreatic cancer, troglitazone has shown cytotoxicity via the JNK pathway and mitochondria-mediated apoptosis which was independent of PPAR-γ. The study reports the absence of marked adverse effects during the in vivo antitumor investigation [33].