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In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.

ABSTRACT: Octamer-binding transcription factor 4 (Oct4) is a core regulator in the retention of stemness, invasive, and self-renewal properties in glioma initiating cells (GSCs) and its overexpression inhibits the differentiation of glioma cells promoting tumor cell proliferation. The Pit-Oct-Unc (POU) domain comprising POU-specific domain (POUS) and POU-type homeodomain (POUHD) subdomains is the most critical part of the Oct4 for the generation of induced pluripotent stem cells from somatic cells that lead to tumor initiation, invasion, posttreatment relapse, and therapeutic resistance. Therefore, the present investigation hunts for natural product inhibitors (NPIs) against the POUHD domain of Oct4 by employing receptor-based virtual screening (RBVS) followed by binding free energy calculation and molecular dynamics simulation (MDS). RBVS provided 13 compounds with acceptable ranges of pharmacokinetic properties and good docking scores having key interactions with the POUHD domain. More Specifically, conformational and interaction stability analysis of 13 compounds through MDS unveiled two compounds ZINC02145000 and ZINC32124203 which stabilized the backbone of protein even in the presence of linker and POUS domain. Additionally, ZINC02145000 and ZINC32124203 exhibited stable and strong interactions with key residues W277, R242, and R234 of the POUHD domain even in dynamic conditions. Interestingly, ZINC02145000 and ZINC32124203 established communication not only with the POUHD domain but also with the POUS domain indicating their incredible potency toward thwarting the function of Oct4. ZINC02145000 and ZINC32124203 also reduced the flexibility and escalated the correlations between the amino acid residues of Oct4 evidenced by PCA and DCCM analysis. Finally, our examination proposed two NPIs that can impede the Oct4 function and may help to improve overall survival, diminish tumor relapse, and achieve a cure not only in deadly disease GBM but also in other cancers with minimal side effects.

SUBMITTER: Nayak C

PROVIDER: S-EPMC8494328 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The nucleocapsid protein (NP) is one of the main proteins out of four structural proteins of coronaviruses including the severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, discovered in 2019. NP packages the viral RNA during virus assembly and is, therefore, indispensable for virus reproduction. NP consists of two domains, i.e., the N- and C-terminal domains. RNA-binding is mainly performed by a binding pocket within the N-terminal domain (NTD). NP represents an important target for drug discovery to treat COVID-19. In this project, we used the Vina LC virtual drug screening software and a ZINC-based database with 210,541 natural and naturally derived compounds that specifically target the binding pocket of NTD of NP. Our aim was to identify coronaviral inhibitors that target NP not only of SARS-CoV-2 but also of other diverse human pathogenic coronaviruses. Virtual drug screening and molecular docking procedures resulted in 73 candidate compounds with a binding affinity below -9 kcal/mol with NP NTD of SARS-CoV-1, SARS-CoV-2, MERS-CoV, HCoV-OC43, HCoV-NL63, HoC-229E, and HCoV-HKU1. The top five compounds that met the applied drug-likeness criteria were then tested for their binding in vitro to the NTD of the full-length recombinant NP proteins using microscale thermophoresis. Compounds (1), (2), and (4), which belong to the same scaffold family of 4-oxo-substituted-6-[2-(4a-hydroxy-decahydroisoquinolin-2-yl)2H-chromen-2-ones and which are derivates of coumarin, were bound with good affinity to NP. Compounds (1) and (4) were bound to the full-length NP of SARS-CoV-2 (aa 1-419) with Kd values of 0.798 (±0.02) µM and 8.07 (±0.36) µM, respectively. Then, these coumarin derivatives were tested with the SARS-CoV-2 NP NTD (aa 48-174). Compounds (1) and (4) revealed Kd-values of 0.95 (±0.32) µM and 7.77 (±6.39) µM, respectively. Compounds (1) and (4) caused low toxicity in human A549 and MRC-5 cell lines. These compounds may represent possible drug candidates, which need further optimization to be used against COVID-19 and other coronaviral infections.

Project description:Enzymatic activity mediated by recombinant human DNA ligase I (hLI), in conjunction with tannin removal procedures, has been applied to a natural-product screen involving approximately 1000 plant extracts and various pure compounds. The primary hLI activity assay involved the measurement of the amount of radiolabelled phosphate in a synthetic nucleic acid hybrid that becomes resistant to alkaline phosphatase as a result of ligation. A bioactivity-guided fractionation scheme resulted in the isolation of ursolic [IC50=100 micrograms/ml (216 microM)] and oleanolic [IC50=100 micrograms/ml (216 microM)] acids from Tricalysia niamniamensis Hiern (Rubiaceae), which demonstrated similar DNA ligase inhibition profiles to other triterpenes such as aleuritolic acid. Protolichesterinic acid [IC50=6 micrograms/ml (20 microM)], swertifrancheside [IC50 = 8 micrograms/ml(11)microM)] and fulvoplumierin [IC50=87 micrograms/ml (357 microM)] represent three additional natural-product structural classes that inhibit hLI. Fagaronine chloride [IC50=10 micrograms/ml (27 micronM] and certain flavonoids are also among the pure natural products that were found to disrupt the activity of the enzyme, consistent with their nucleic acid intercalative properties. Further analyses revealed that some of the hLI-inhibitory compounds interfered with the initial adenylation step of the ligation reaction, indicating a direct interaction with the enzyme protein. However, in all cases, this enzyme-inhibitor interaction did not disrupt the DNA relaxation activity mediated by hLI. These results indicate that, although the same enzyme active site may be involved in both enzyme adenylation and DNA relaxation, inhibitors may exert allosteric effects by inducing conformational changes that disrupt only one of these activities. Studies with inhibitors are important for the assignment of specific cellular functions to these enzymes, as well as for their development into clinically useful antitumour agents.

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In silico identification of natural product inhibitors against Octamer-binding transcription factor 4 (Oct4) to impede the mechanism of glioma stem cells.

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