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.

Background: Casein kinase 1 epsilon (CK1ε) plays a critical role in cancer progression by activating oncogenic signaling pathways, making it a target for cancer therapy. However, no inhibitors are currently available for clinical use, highlighting the need for novel therapeutic candidates. Methods: This study aimed to identify potential CK1ε inhibitors. To achieve this, a modified version of a previously reported pharmacophore model was applied to an ultra-large database of over 100 million compounds for virtual screening. Hits were filtered based on drug-likeness and pH-dependent pharmacophore compliance and then grouped according to their structural core. A representative compound from each structural group underwent molecular dynamic (MD) simulations and binding free energy calculations to predict its stability and affinity, allowing extrapolation of the results to the entire set of candidates. Results: Pharmacophore matching initially identified 290 compounds. After energy minimization, and an assessment of drug-likeness and pharmacophore compliance, we selected 29 structurally related candidates. MD simulations showed that most of the compounds representative of structural groups had stable binding modes, favorable intermolecular interactions, and free energies comparable to those of previously reported CK1ε inhibitors. An analysis of additional members of the most promising structural group showed that two 2,4-diaminopyrimidine-based compounds likely inhibit CK1ε. Conclusions: These findings provide structural insights into the design of CK1ε inhibitors, supporting compound optimization and the eventual development of targeted cancer therapeutics.

Immunotherapy has become a cornerstone in cancer treatment, with anti-PD-L1 antibodies effectively used across various cancers. Although these therapies have shown success, antibodies face limitations in bioavailability compared to low molecular mass compounds. An alternative strategy is to stabilize PD-L1 homodimers to prevent their immunosuppressive activity. The homodimer interface forms a tunnel-like cavity that can accommodate small molecules. However, no small drugs targeting PD-L1 homodimers have been approved for cancer treatment. Drug repurposing offers a promising approach to bridge this gap. In this study, we sought to identify potential PD-L1 inhibitors among FDA-approved drugs using virtual screening, followed by molecular docking, molecular dynamics simulations, and MM/PBSA binding energy calculations. Our results indicate that daclatasvir, an FDA-approved antiviral for hepatitis C, forms a stable and energetically favorable complex with the PD-L1 homodimer, suggesting it as a promising candidate for further investigation in cancer immunotherapy. Due to its symmetry, daclatasvir simultaneously interacts with both PD-L1 monomers in an equivalent manner, bridging the dimer interface. Its biphenyl core anchors at the center of the tunnel, the imidazole rings position at the entrances, and the pyrrolidine rings remain exposed to the solvent. Our in-depth characterization of the binding mode of daclatasvir clarifies its binding mechanism, and recent experimental findings have also indicated that daclatasvir binds to PD-L1, supporting its potential in this new context. Resumen. La inmunoterapia se ha convertido en una piedra angular en el tratamiento del cáncer, y los anticuerpos anti-PD-L1 se utilizan eficazmente en varios tipos de cáncer. Aunque estas terapias han demostrado ser exitosas, los anticuerpos enfrentan limitaciones de biodisponibilidad en comparación con los compuestos de baja masa molecular. Una alternativa al uso de anticuerpos consiste en estabilizar homodímeros de PD-L1 para impedir su función inmunosupresora. La interfase de los homodímeros de PD-L1 constituye un túnel que puede alojar moléculas de baja masa molecular. Sin embargo, no existen moléculas pequeñas dirigidas al homodímero de PD-L1 con aprobación regulatoria para el tratamiento del cáncer. El reposicionamiento de fármacos ofrece un enfoque prometedor para cerrar esta brecha. En este estudio, buscamos identificar potenciales inhibidores de PD-L1 entre los fármacos aprobados por la FDA mediante cribado virtual, acoplamientos moleculares, simulaciones de dinámica molecular y cálculos de energía de unión MM/PBSA. Nuestros resultados indican que daclatasvir, un antiviral aprobado por la FDA para la hepatitis C, forma un complejo estable y energéticamente favorable con el homodímero PD-L1, lo que sugiere que es un candidato prometedor en la inmunoterapia contra el cáncer. Debido a su simetría, daclatasvir puede interactuar simultáneamente y de la misma manera con ambos monómeros de PD-L1, estabilizando la unión. El núcleo bifenilo de daclatasvir se aloja en el centro del túnel del homodímero, los anillos de imidazol se colocan en las entradas, y los anillos de pirrolidina permanecen expuestos al solvente. Nuestra caracterización detallada del modo de unión de daclatasvir aclara su mecanismo de interacción. Además, hallazgos experimentales recientes indican que daclatasvir se une a PD-L1, lo que respalda su potencial en este nuevo contexto.

Immunotherapy has become a cornerstone in cancer treatment, with anti-PD-L1 antibodies effectively used across various cancers. Although these therapies have shown success, antibodies face limitations in bioavailability compared to low molecular mass compounds. An alternative strategy is to stabilize PD-L1 homodimers to prevent their immunosuppressive activity. The homodimer interface forms a tunnel-like cavity that can accommodate small molecules. However, no small drugs targeting PD-L1 homodimers have been approved for cancer treatment. Drug repurposing offers a promising approach to bridge this gap. In this study, we sought to identify potential PD-L1 inhibitors among FDA-approved drugs using virtual screening, followed by molecular docking, molecular dynamics simulations, and MM/PBSA binding energy calculations. Our results indicate that daclatasvir, an FDA-approved antiviral for hepatitis C, forms a stable and energetically favorable complex with the PD-L1 homodimer, suggesting it as a promising candidate for further investigation in cancer immunotherapy. Due to its symmetry, daclatasvir simultaneously interacts with both PD-L1 monomers in an equivalent manner, bridging the dimer interface. Its biphenyl core anchors at the center of the tunnel, the imidazole rings position at the entrances, and the pyrrolidine rings remain exposed to the solvent. Our in-depth characterization of the binding mode of daclatasvir clarifies its binding mechanism, and recent experimental findings have also indicated that daclatasvir binds to PD-L1, supporting its potential in this new context.

La caseína cinasa 1 épsilon (CK1ε) es una enzima que promueve la progresión de diversos tumores, por lo que es considerada una diana terapéutica. Sin embargo, aún no existen fármacos con uso clínico contra CK1ε. En este estudio, utilizamos una estrategia de cribado virtual para identificar potenciales inhibidores de CK1ε. Utilizando recursos de supercómputo para realizar simulaciones de dinámica molecular, identificamos las interacciones que median la unión entre CK1ε e inhibidores reportados. Con estos datos, generamos un modelo de farmacóforo que empleamos para identificar candidatos dentro de grandes bases de compuestos. A continuación, realizamos acoplamientos moleculares seguidos de cálculos de propiedades ADMET y microespecies predominantes. Finalmente, usamos nuevamente recursos de supercómputo para caracterizar detalladamente el modo de unión de los compuestos más prometedores para inhibir a CK1ε, mediante simulaciones de dinámica molecular. Como resultado, identificamos tres compuestos con potencial actividad inhibitoria de CK1ε. Nuestros hallazgos ilustran cómo el proceso de cribado virtual, empleando modelos de farmacóforo y simulaciones de dinámica molecular realizadas con recursos de supercómputo permite identificar compuestos con potencial actividad inhibitoria sobre CK1ε. Además, discutimos el papel del supercómputo en la viabilidad de este tipo de estrategias, particularmente en estudios que requieren realizar simulaciones de dinámica molecular. La estrategia empleada en este trabajo aprovecha las capacidades de supercomputadoras para el descubrimiento de nuevos fármacos.