Computational and Biophysical Characterization of Heterocyclic Derivatives of Anthraquinone against Human Aurora Kinase A
Ontology highlight
ABSTRACT:
SUBMITTER: Singh M
PROVIDER: S-EPMC9647706 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.
| S-EPMC6872649 | biostudies-literature
Project description:Inhibiting protein-protein interactions of the Myc family is a viable pharmacological strategy for modulation of the levels of Myc oncoproteins in cancer. Aurora A kinase (AurA) and N-Myc interaction is one of the most attractive targets of this strategy because formation of this complex blocks proteasomal degradation of N-Myc in neuroblastoma. Two crystallization studies have captured this complex (PDB IDs: 5g1x, 7ztl), partially resolving the AurA interaction region (AIR) of N-Myc. Prompted by the missing N-Myc fragment in these crystal structures, we modeled the complete structure between AurA and N-Myc, and comprehensively analyzed how the incomplete and complete N-Myc behave in complex by molecular dynamics simulations. Molecular dynamics simulations of the incomplete PDB complex (5g1x) repeatedly showed partial dissociation of the short N-Myc fragment (61-89) from the kinase. The missing N-Myc (19-60) fragment was modeled utilizing the N-terminal lobe of AurA as the protein-protein interaction surface, wherein TPX2, a well-known partner of AurA, also binds. Binding free energy calculations along with flexibility analysis confirmed that the complete AIR of N-Myc stabilizes the complex, accentuating the N-terminal lobe of AurA as a binding site for the missing N-Myc fragment (19-60). We further generated additional models consisting of only the missing N-Myc (19-60), and the fused form of TPX2 (7-43) and N-Myc (61-89). These partners also formed more stable interactions with the N-terminal lobe of AurA than did the incomplete N-Myc fragment (61-89) in the 5g1x complex. Altogether, this study provides structural insights into the involvement of the N-terminus of the AIR of N-Myc and the N-terminal lobe of AurA in formation of a stable complex, reflecting its potential for effective targeting of N-Myc.
| S-EPMC10603048 | biostudies-literature
Project description:Periodontal disease (PD) is multifactorial oral disease that damages tooth-supporting tissue. PD treatment includes proper oral hygiene, deep cleaning, antibiotics therapy, and surgery. Despite the availability of basic treatments, some of these are rendered undesirable in PD treatment due to side effects and expense. Therefore, the aim of the present study is to develop novel molecules to combat the PD triggering pathogens. The study involved the synthesis of 4-((5-(substituted-phenyl)-1,3,4-oxadiazol-2-yl)methoxy)benzamidine (5a-e), by condensation of 2-(4-carbamimidoylphenoxy)acetohydrazide (3) with different aromatic acids; and synthesis of 4-((4-(substituted benzylideneamino)-4H-1,2,4-triazol-3-yl)methoxy)benzamidine (6a-b) by treatment of compound 3 with CS2 followed by hydrazination and a Schiff reaction with different aromatic aldehydes. Synthesized compounds were characterized based on the NMR, FTIR, and mass spectrometric data. To assess the effectiveness of the newly synthesized compound in PD, new compounds were subjected to antimicrobial evaluation against P. gingivalis and E. coli using the micro-broth dilution method. Synthesized compounds were also subjected to cytotoxicity evaluation against HEK-293 cells using an MTT assay. The present study revealed the successful synthesis of heterocyclic derivatives of benzamidine with significant inhibitory potential against P. gingivalis and E. coli. Synthesized compounds exhibited minimal to the absence of cytotoxicity. Significant antimicrobial potential and least/no cytotoxicity of new heterocyclic analogs of benzamidine against PD-triggering bacteria supports their potential application in PD treatment.
| S-EPMC9952644 | biostudies-literature
Project description:Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of sensitive cells. Bioinformatic analyses showed that JQ1-sensitive cells could also respond to Aurora Kinase A inhibition which indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibition could potentiate the efficacy of TMZ or could be combined with Aurora Kinase inhibitors in MYCN-elevated GBM.
2019-12-05 | GSE138942 | GEO
Project description:Anthraquinone derivatives are identified for their immune-boosting, anti-inflammatory, and anti-viral efficacy. Hence, the present study aimed to investigate the reported anthraquinone derivatives as immune booster molecules in COVID-19 infection and evaluate their binding affinity with three reported targets of novel coronavirus i.e. 3C-like protease, papain-like protease, and spike protein. The reported anthraquinone derivatives were retrieved from an open-source database and filtered based on a positive druglikeness score. Compounds with positive druglikeness scores were predicted for their targets using DIGEP-Pred and the interaction among modulated proteins was evaluated using STRING. Further, the associated pathways were recorded concerning the Kyoto Encyclopedia of Genes and Genomes pathway database. Finally, the docking was performed using autodock4 to identify the binding efficacy of anthraquinone derivatives with 3C-like protease, papain-like protease, and spike protein. After docking the pose of ligand scoring minimum binding energy was chosen to visualize the ligand-protein interaction. Among 101 bioactives, 36 scored positive druglikeness score and regulated multiple pathways concerned with immune modulation and (non-) infectious diseases. Similarly, docking study revealed torososide B to possess the highest binding affinity with papain-like protease and 3C-like protease and 1,3,6-trihydroxy-2-methyl-9,10-anthraquinone-3-O-(6'-O-acetyl)-β-D-xylopyranosyl-(1 → 2)-β-D-glucopyranoside with spike protein.
| S-EPMC7414902 | biostudies-literature
Project description:AIM: To characterize the structural features of quinazoline-based Aurora B inhibitors that influence its inhibitor activity. METHODS: Two geometrical methods, Method 1 and Method 2, were used to develop the 3D-QSAR models. The most active ligand was used as the template for the alignment of all the ligands in Method 1, and a conformer of the cocrystal ligand was used as the template for the alignment of all the ligands in Method 2. RESULTS: The models suggest that highly active ligands can be designed by varying the R1 substituent at position 7 of the quinazoline ring with positively charged, bulky, hydrophobic groups, while bulky and hydrophobic groups around the thiazole ring are desirable for higher activity. CONCLUSION: This study emphasizes that the bioactive conformer is rather different from the minima. The steric, electrostatic, and hydrophobic field effects contribute to its inhibitory activity.
| S-EPMC4002836 | biostudies-literature
Project description:Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important in understanding Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation site clustering, protein localization, protein structure, and species conservation. We validate the microtubule-associated proteins Clasp2, Elys, tubulin tyrosine ligase-like polyglutamylase residues 330-624 and spindle and centriole associated protein 1, residues 549-855 (SPICE1), as Aurora A and B kinases substrates in vitro. We also demonstrate that SPICE1 localization is regulated by Aurora kinases during mitosis. In the absence of Aurora kinase activity, SPICE1 remains at centrioles but does not target to the spindle. Similarly, a nonphosphorylatable SPICE1 mutant no longer localizes to the spindle. Finally, we show that misregulating SPICE1 phosphorylation results in abnormal centriole number, spindle multipolarity, and chromosome alignment defects. Overall, our work indicates that temporal and spatial Aurora kinase-mediated regulation of SPICE1 is important for correct chromosome segregation. In addition, our work provides a database-search tool that enables rapid identification of Aurora kinase substrates.
| S-EPMC6589576 | biostudies-literature
Project description:The aberrant function of c-Met kinase signaling pathway is ubiquitously involved in a broad spectrum of human cancers; thus, a strong rationale exists for targeting the kinase pathway in cancer therapy. Via integration of computational and experimental studies, anthraquinone derivatives were identified for the first time as potent c-Met kinase inhibitors in this research. The aberrant activation of the c-Met kinase pathway results from (TPR)-Met, MET gene mutation, or amplification and a hepatocyte growth factor (HGF)/scatter factor-dependent autocrine or paracrine mechanism. However, anthraquinone derivatives exclusively suppressed c-Met phosphorylation stimulated by HGF in A549 cells, indicating that the compounds possess the ability to block the extracellular HGF-dependent pathway. A surface plasmon resonance assay revealed that the most potent compound, 2a, shows a high binding affinity for HGF with an equilibrium dissociation constant of 1.95 μM. The dual roles of compound 2a demonstrate the potency of anthraquinone derivatives and provide a new design solution for the c-Met kinase signaling pathway.
| S-EPMC4027229 | biostudies-literature
Project description:Protein kinases are important drug targets in human cancers, inflammation and metabolic diseases. Docking studies was performed for all the benzimidazopyrimidine and coumarin substituted benzimidazopyridimine derivatives with human Aurora A kinase target (3FDN) employing flexible ligand docking approach by using AutoDock 4.2. All the compounds were found to have minimum binding energy ranging from -6.26 to -9.29 kJ/mol. Among the molecules tested for docking study, 10-(6-Bromo-2-oxo- 2H-chromen-4-ylmethyl)-2-isopropyl-10H-benzo[4,5]imidazo[1,2-a]pyrimidin-4-one (2k) showed minimum binding energy (-9.29 kJ/mol) with ligand efficiency of -0.31. All the ligands were docked deeply within the binding pocket region of 3FDN showing hydrogen bonds with Ala 213 and Asn 261. The docking study results showed that these derivatives are excellent inhibitor of human Aurora A kinase target; and also all these docked compounds have good inhibition constant, vdW + Hbond + desolv energy with best RMSD value.
| S-EPMC4070038 | biostudies-literature
Project description:Chromosome segregation is an extensively choreographed process yet errors still occur frequently in female meiosis, leading to implantation failure, miscarriage or offspring with developmental disorders. Aurora kinase C (AURKC) is a component of the chromosome passenger complex and is highly expressed in gametes. Studies in mouse oocytes indicate that AURKC is required to regulate chromosome segregation during meiosis I; however, little is known about the functional significance of AURKC in human oocytes. Three splice variants of AURKC exist in testis tissue. To determine which splice variants human oocytes express, we performed quantitative real-time PCR using single oocytes and found expression of all three variants. To evaluate the functional differences between the variants, we created green fluorescent protein-tagged constructs of each variant to express in oocytes from Aurkc(-/-) mice. By quantifying metaphase chromosome alignment, cell cycle progression, phosphorylation of INCENP and microtubule attachments to kinetochores, we found that AURKC_v1 was the most capable of the variants at supporting metaphase I chromosome segregation. AURKC_v3 localized to chromosomes properly and supported cell cycle progression to metaphase II, but its inability to correct erroneous microtubule attachments to kinetochores meant that chromosome segregation was not as accurate compared with the other two variants. Finally, when we expressed the three variants simultaneously, error correction was more robust than when they were expressed on their own. Therefore, oocytes express three variants of AURKC that are not functionally equivalent in supporting meiosis, but fully complement meiosis when expressed simultaneously.
| S-EPMC4518136 | biostudies-literature