RESUMEN
This study evaluates radio-iodinated anastrozole ([125I]anastrozole) and epirubicin ([125I]epirubicin) for AKT1-targeted breast cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds' binding affinities and mechanisms to the AKT1 enzyme, compared to the co-crystallized ligand, a known AKT1 inhibitor. Molecular docking results show that [125I]epirubicin has the highest ΔGbind (-11.84 kcal/mol), indicating a superior binding affinity compared to [125I] anastrozole (-10.68 kcal/mol) and the co-crystallized ligand (-9.53 kcal/mol). Molecular dynamics (MD) simulations confirmed a stable interaction with the AKT1 enzyme, with [125I]anastrozole and [125I]epirubicin reaching stability after approximately 68 ns with an average RMSD of around 2.2 Å, while the co-crystallized ligand stabilized at approximately 2.69 Å after 87 ns. RMSF analysis showed no significant shifts in residues or segments, with consistent patterns and differences of less than 2 Å, maintaining enzyme stability. The [125I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions, while [125I]anastrozole consistently formed three H-bonds. The average Rg values for both complexes were ~16.8 ± 0.1 Å, indicating no significant changes in the enzyme's compactness, thus preserving structural integrity. These analyses reveal stable binding and minimal structural perturbations, suggesting the high potential for AKT1 inhibition. MM-PBSA calculations confirm the potential of these radio-iodinated compounds as AKT1 inhibitors, with [125I]epirubicin exhibiting the most favorable binding energy (-23.57 ± 0.14 kcal/mol) compared to [125I]anastrozole (-20.03 ± 0.15 kcal/mol) and the co-crystallized ligand (-16.38 ± 0.14 kcal/mol), highlighting the significant role of electrostatic interactions in stabilizing the complex. The computational analysis shows [125I]anastrozole and [125I]epirubicin may play promising roles as AKT1 inhibitors, especially [125I]epirubicin for its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the AKT1 enzyme. Nevertheless, it is crucial to validate these computational predictions through in vitro and in vivo studies to thoroughly evaluate the therapeutic potential and viability of these compounds for AKT1-targeted breast cancer treatment.
Asunto(s)
Anastrozol , Neoplasias de la Mama , Epirrubicina , Radioisótopos de Yodo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Proteínas Proto-Oncogénicas c-akt , Radiofármacos , Epirrubicina/química , Epirrubicina/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Humanos , Radioisótopos de Yodo/química , Radiofármacos/química , Radiofármacos/farmacología , Anastrozol/química , Anastrozol/uso terapéutico , Anastrozol/farmacología , Femenino , Ligandos , Unión Proteica , Simulación por ComputadorRESUMEN
Targeted protein degradation using small molecules is an intriguing strategy for drug development. The marine sesterterpene compound MHO7 had been reported to be a potential ERα degradation agent. In order to further improve its biological activity, two series of novel MHO7 derivatives with long side chains were designed and identified as novel selective estrogen receptor down-regulators (SERDs). The growth inhibition activity of the novel SERD compounds were significantly affected by the type and length of the side chain. Most of the derivatives were significantly more potent than MHO7 against both drug-sensitive and drug-resistant breast cancer cells. Among them, compound 16a, with IC50 values of 0.41 µM against MCF-7 cell lines and 9.6-fold stronger than MHO7, was the most potential molecule. A whole-genome transcriptomic analysis of MCF-7 cells revealed that the mechanism of 16a against MCF-7 cell was similar with that of MHO7. The estrogen signaling pathway was the most affected among the disturbed genes, but the ERα degradation activity of 16a was observed higher than that of MHO7. Other effects of 16a were confirmed similar with MHO7, which means that the basic mechanisms of the derivatives are the same with the ophiobolin backbone, i.e. the degradation of ERα is mediated via proteasome-mediated process, the induction of apoptosis and the cell cycle arrest at the G1 phase. Meanwhile, a decrease of mitochondrial membrane potential and an increase of cellular ROS were also detected. Based on these results, as a novel modified ophiobolin derived compound, 16a may warrant further exploitation as a promising SERD candidate agent for the treatment of breast cancer.
Asunto(s)
Antineoplásicos/síntesis química , Productos Biológicos/química , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Sesterterpenos/síntesis química , Anastrozol/química , Anastrozol/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Productos Biológicos/farmacología , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Humanos , Letrozol/química , Letrozol/farmacología , Células MCF-7 , Simulación del Acoplamiento Molecular , Unión Proteica , Proteolisis , Clorhidrato de Raloxifeno/química , Clorhidrato de Raloxifeno/farmacología , Especies Reactivas de Oxígeno/metabolismo , Sesterterpenos/farmacología , Transducción de Señal , Relación Estructura-Actividad , Tamoxifeno/química , Tamoxifeno/farmacologíaRESUMEN
In the present study, we employ fluorescence spectroscopy, dynamic light scattering, and molecular docking methods. Binding of anticancer drug anastrozole with human lysozyme (HL) is studied. Binding of anastrozole to HL is moderate but spontaneous. There is anastrozole persuaded hydrodynamic change in HL, leading to molecular compaction. Binding of anastrozole to HL also decreased in vitro lytic activity of HL. Molecular docking results suggest the electrostatic interactions and van der Waals forces played key role in binding interaction of anastrozole near the catalytic site. Binding interaction of anastrozole to proteins other than major transport proteins in blood can significantly affect pharmacokinetics of this molecule. Hence, rationalizing drug dosage is important. This study also points to unrelated effects that small molecules bring in the body that are considerable and need thorough investigation.
Asunto(s)
Anastrozol/química , Antineoplásicos/química , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Muramidasa/química , Análisis Espectral , Anastrozol/farmacología , Antineoplásicos/farmacología , Activación Enzimática , Humanos , Conformación Molecular , Estructura Molecular , Muramidasa/metabolismo , Unión Proteica , Relación Estructura-ActividadRESUMEN
BACKGROUND AND OBJECTIVE: Topoisomerase TOP-IIA (TTOP-IIA) is widely used as a significant target for cancer therapeutics because of its involvement in cell proliferation. Steroidal drugs have been suggested for breast cancer treatment as aromatase enzymes inhibitors . TTOP-IIA inhibitors can be used as a target for the development of new cancer therapeutics. MATERIALS AND METHODS: In this study, we conducted a docking study on steroidal drugs Anastrozole (ANA), Letrozole (LET), and exemestane (EXE) with TTOP-IIA to explore the therapeutic area of these drugs. RESULTS: The binding interaction of EXE drug had significant docking interaction which is followed by ANA and LET. Thus, all these drugs could be used to inhibit the TTOP-IIA mediated cell proliferation and could be a hope to treat the other types of cancers. Among all three tested steroidal drugs, EXE showed binding energy -7.05 kcal/mol, hydrogen bond length1.78289 Å and amino acid involved in an interaction was A: LYS723:HZ3 -: UNK1:O6. CONCLUSION: The obtained data showed the most significant binding interaction analyzed with the tested enzyme. Thus, in vitro laboratory experimentation and in vivo research are necessary to put forward therapeutic repositioning of these drugs to establish them as a broad spectrum potential anticancer drugs.
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Asunto(s)
Antineoplásicos/química , Antineoplásicos/metabolismo , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , ADN-Topoisomerasas de Tipo II/química , ADN-Topoisomerasas de Tipo II/metabolismo , Anastrozol/química , Anastrozol/metabolismo , Androstadienos/química , Androstadienos/metabolismo , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Simulación por Computador , Femenino , Humanos , Letrozol/química , Letrozol/metabolismo , Conformación ProteicaRESUMEN
DNA stands as the primary purpose of many anticancer drugs and according to the performed research on this field, some certain changes contain crucial functionalities in the regulated transcription of DNA. Therefore, the interaction between anticancer drugs and DNA play an important role in understanding their function and also provide a better groundwork for producing more efficient and newer drugs. Here, the interaction between Docetaxel (DO) and calf thymus DNA (ct DNA), in the presence and absence of Anastrozole (AN), has been examined through the usage of different methods that include isothermal titration calorimetry, multi-spectroscopic, viscometry, and molecular docking techniques. Interaction studies have been performed by preparing different molar ratios of DO with the constant ct DNA and AN concentration at pHâ¯=â¯6.8. The binding constants have been calculated to be 7.93â¯×â¯104â¯M-1 and 6.27â¯×â¯104â¯M-1, which indicate the strong binding of DO with ct DNA double helix in the absence and presence of AN, respectively. Thermodynamic parameters, which were obtained from fluorescence spectroscopy and isothermal titration calorimetry, have suggested that the binding of DO and AN to ct DNA as binary and ternary systems have been mainly driven by the electrostatic interactions. The relative viscosity of ct DNA has increased upon the addition of DO and AN, which confirms the interaction mode. A competitive binding study has reported that the enhanced emission intensity of ethidium bromide (EB) and acridine orange (AO), in the presence of ct DNA, have been quenched through the addition of DO and Anastrozole as binary and ternary systems. As it is indicated by these findings, DO is capable of displacing EB and AO from their binding site in ct DNA; hence, it can be concluded that DO and AN are able to intercalate into the base pairs of ct DNA in binary and ternary systems. Molecular docking studies have corroborated the mentioned experimental results.
Asunto(s)
Anastrozol/metabolismo , Simulación por Computador , ADN/metabolismo , Docetaxel/metabolismo , Anastrozol/química , Unión Competitiva , Calorimetría , ADN/química , Docetaxel/química , Cinética , Modelos Moleculares , Desnaturalización de Ácido Nucleico , Concentración Osmolar , Dispersión de Radiación , Espectrometría de Fluorescencia , Termodinámica , ViscosidadRESUMEN
This report details the preparation of anastrozole (ATZ) reservoir-type intravaginal ring (IVR) and the detection of the concentration of ATZ in beagle dog plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS). An ATZ reservoir-type IVR which included ATZ silicone elastomer core and a nonactive silicone layer was manufactured by reaction injection moulding at 80°C for 20 min. An in vitro release experiment was performed under sink conditions and the samples were determined by high-performance liquid chromatography. A bioanalytical method was developed and validated for determination of ATZ in beagle dog plasma for IVR development. The analytical method consisted of the extraction of plasma samples and determination of ATZ by LC-MS/MS using buspirone as the internal standard. Separation was achieved on a Kinetex-C18 110A column (3 × 30 mm, 2.6 µm, Phenomenex) using step-gradient mobile phase and an isocratic flow rate consisting of formic acid. Protonated ions formed by a turboion spray in the positive mode was used to detect the analyte (ATZ) and internal standard. The MS-MS detection was performed on a triple quadrupole mass spectrometer equipped with electrospray ionization source. The mass spectrometer was operated in the multiple reaction monitoring mode. The mass transition ion-pair was followed as m/z from 294.10 to 225.08 for anastrozole and m/z from 386.23 to 122.11 for buspirone. The results proved that the correlation between in vitro and in vivo analyses was relatively good.