Repositioning of Etravirine as a Potential CK1ε Inhibitor by Virtual Screening

Abstract

CK1ε is a key regulator of WNT/β-catenin and other pathways that are linked to tumor progression; thus, CK1ε is considered a target for the development of antineoplastic therapies. In this study, we performed a virtual screening to search for potential CK1ε inhibitors. First, we characterized the dynamic noncovalent interactions profiles for a set of reported CK1ε inhibitors to generate a pharmacophore model, which was used to identify new potential inhibitors among FDA-approved drugs. We found that etravirine and abacavir, two drugs that are approved for HIV infections, can be repurposed as CK1ε inhibitors. The interaction of these drugs with CK1ε was further examined by molecular docking and molecular dynamics. Etravirine and abacavir formed stable complexes with the target, emulating the binding behavior of known inhibitors. However, only etravirine showed high theoretical binding affinity to CK1ε. Our findings provide a new pharmacophore for targeting CK1ε and implicate etravirine as a CK1ε inhibitor and antineoplastic agent.

Exploring Darunavir, Rilpivirine and Etravirine as Potential Therapies for Bladder Cancer: Efficacy and Synergistic Effects

“…This is following the literature found, since ETV has been the most studied drug among these three. A potential mode of action that has been explored is the inhibition of casein kinase 1 ε (CK1ε), which is an enzyme included in a family of enzymes that are involved in signal transduction pathways [ 33 ]. This enzyme is a positive regulator of the WNT/β-catenin pathway, activated by WNT and responsible for the phosphorylation of the Dishevelled protein that ensures the stability of β-catenin by inhibiting its degradation complex [ 34 ].…”

“…The inhibition of CK1ε has, therefore, been explored and has demonstrated results in inducing cell cycle arrest and apoptosis in cancer cells, and ETV has been proposed as an inhibitor of this molecule. This drug was selected among the FDA-approved drug library in a virtual screening as being highly capable of binding to CK1ε, with similar results to the CK1ε umbralisib, showing the promise of ETV in inhibiting this enzyme [ 33 ], which could be a path that relates to the results in the present article. Another mode of action that could be behind ETV’s capacity to decrease the viability of bladder cancer cells is the inhibition of the human anterior gradient protein 2 homolog (AGR2).…”

In silico screening based on chemoinformatics and molecular docking of trypanothione reductase inhibitors from Trypanosoma cruzi

“…2D structures were drawn with Marvin Sketch Chemaxon (https://okta.chemaxon.com/) software and protonation states were calculated at pH 7.4. Subsequently, the 3D structures of the molecules under study were obtained and optimized at a semi-empirical PM3 level with the Spartan program (Córdova-Bahena et al, 2022;Prieto et al, 2022). The three-dimensional structure of the crystal of the enzyme trypanothione reductase of Trypanosoma cruzi cocrystallized with its endogenous ligand trypanothione and the flavin adenine dinucleotide coenzyme (FAD) was downloaded from the Protein Data Bank repository with the code 1BZL (Bond et al, 1999;Battista et al, 2020).…”

“…The three-dimensional structure of the crystal of the enzyme trypanothione reductase of Trypanosoma cruzi cocrystallized with its endogenous ligand trypanothione and the flavin adenine dinucleotide coenzyme (FAD) was downloaded from the Protein Data Bank repository with the code 1BZL (Bond et al, 1999;Battista et al, 2020). The preparation of the protein was carried out with the Molegro Virtual Docker program (Córdova-Bahena et al, 2022;Prieto et al, 2022), water molecules were removed, druggable cavities were detected, and the catalytic site of the A chain was selected for docking molecular studies with a search sphere of 10 Å radius, with the coordinates X: 24.21, Y: 9.46, Z: -4.01 and a grid of 0.20 Å.…”

“…In each method, 10 runs were performed, a maximum of 1500 interactions and an initial population of 50 poses (Córdova-Bahena et al, 2022;Prieto et al, 2022). The method to perform the docking molecular consisting of the function and search algorithm, was chosen considering as inclusion criterion a rmsd value ≤ 2.0 (Houston & Walkinshaw., 2013;Ballón et al, 2019), obtained for ligand coupled with respect to the position of the co-crystallized ligand as shown in Figure 1A.…”