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  1. Article ; Online: Transcription factor NF-κB as target for SARS-CoV-2 drug discovery efforts using inflammation-based QSAR screening model.

    Kanan, Tarek / Kanan, Duaa / Al Shardoub, Ebrahim Jaafar / Durdagi, Serdar

    Journal of molecular graphics & modelling

    2021  Volume 108, Page(s) 107968

    Abstract: NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The ... ...

    Abstract NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The aim of this study was to identify potential anti-inflammation lead molecules that target NF-κB using a quantitative structure-activity relationships (QSAR) model of currently used and investigated anti-inflammatory drugs as the basis for screening. We applied an integrated approach by starting with the inflammation-based QSAR model to screen three libraries containing more than 220,000 drug-like molecules for the purpose of finding potential drugs that target the NF-κB/IκBα p50/p65 (RelA) complex. We also used QSAR models to rule out molecules that were predicted to be toxic. Among screening libraries, 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamics (MD) simulations and free energy calculations. We have discovered five hit ligands with highly predicted anti-inflammation activity and nearly no predicted toxicities which had strongly favorable protein-ligand interactions and conformational stability at the binding pocket compared to a known NF-κB inhibitor (procyanidin B2). We propose these hit molecules as potential NF-κB inhibitors which can be further investigated in pre-clinical studies against SARS-CoV-2 and may be used as a scaffold for chemical optimization and drug development efforts.
    MeSH term(s) COVID-19 ; Drug Discovery ; Humans ; Inflammation/drug therapy ; NF-kappa B/metabolism ; Quantitative Structure-Activity Relationship ; SARS-CoV-2
    Chemical Substances NF-kappa B
    Language English
    Publishing date 2021-06-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1396450-1
    ISSN 1873-4243 ; 1093-3263
    ISSN (online) 1873-4243
    ISSN 1093-3263
    DOI 10.1016/j.jmgm.2021.107968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3491: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: A Successful Model for an Introductory Oncology Teaching Conference and Its Impact on Preclinical and Clinical Medical Students.

    Kanan, Duaa / Kanan, Tarek / Kalyenci, Nursena / Nanah, Abdel Rahman / Tarbaghia, Marwa / Ekmekci, Betigul / Çelik, Serkan / Öven, Bala Başak

    JCO oncology practice

    2022  Volume 18, Issue 6, Page(s) e907–e914

    Abstract: Purpose: Oncology education at medical schools is often fragmented, under-represented, and nonstandardized. Medical students lack essential knowledge, skills, and attitudes necessary for them to provide optimal primary care to patients with cancer upon ... ...

    Abstract Purpose: Oncology education at medical schools is often fragmented, under-represented, and nonstandardized. Medical students lack essential knowledge, skills, and attitudes necessary for them to provide optimal primary care to patients with cancer upon graduation.
    Methods: In this study, we designed and assessed the impact of a compact oncology teaching conference on medical students. The conference covered topics in cancer biology, public health, diagnosis, patient management, treatment, and communication skills. Medical students completed voluntary presurveys and postsurveys regarding their perceived knowledge, attitudes, and perspectives. The event was promoted by student groups, particularly our ASCO Oncology Student Interest Group, and took place online.
    Results: A total of 228 responses from medical students representing 50 universities were analyzed. We revealed significant baseline confidence and perceived knowledge deficits especially in diagnosis and patient management, and treatment modalities. Our conference positively affected self-assessed knowledge acquisition among students, with the most pronounced differences seen in diagnosis and patient management (2.51 ± 1
    Conclusion: We demonstrated that a compact teaching conference resulted in significant improvements in students' confidence and perceived knowledge about oncology. Our successful teaching model can be adapted and implemented at medical schools globally. Development and evaluation of teaching programs are important to urgently reform undergraduate medical education in oncology.
    MeSH term(s) Curriculum ; Education, Medical, Undergraduate/methods ; Humans ; Medical Oncology/education ; Neoplasms/therapy ; Students, Medical
    Language English
    Publishing date 2022-02-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3028198-2
    ISSN 2688-1535 ; 2688-1527
    ISSN (online) 2688-1535
    ISSN 2688-1527
    DOI 10.1200/OP.21.00463
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 7198: Show issues Location:
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  3. Article ; Online: An Integrated in silico Approach and in vitro Study for the Discovery of Small-Molecule USP7 Inhibitors as Potential Cancer Therapies.

    Kanan, Duaa / Kanan, Tarek / Dogan, Berna / Orhan, Muge Didem / Avsar, Timucin / Durdagi, Serdar

    ChemMedChem

    2020  Volume 16, Issue 3, Page(s) 555–567

    Abstract: The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous ... ...

    Abstract The ubiquitin-specific protease 7 (USP7) is a highly promising well-validated target for a variety of malignancies. USP7 is critical in regulating the tumor suppressor p53 along with numerous epigenetic modifiers and transcription factors. Previous studies showed that USP7 inhibitors led to increased levels of p53 and anti-proliferative effects in hematological and solid tumor cell lines. Thus, this study aimed to identify potent and safe USP7 hit inhibitors as potential anti-cancer therapeutics via an integrated computational approach that combines pharmacophore modeling, molecular docking, molecular dynamics (MD) simulations and post-MD free energy calculations. In this study, the crystal structure of USP7 has been extensively investigated using a combination of three different chemical pharmacophore modeling approaches. We then screened ∼220.000 drug-like small molecule library and the hit ligands predicted to be nontoxic were evaluated further. The identified hits from each pharmacophore modeling study were further examined by 1-ns short MD simulations and MM/GBSA free energy analysis. In total, we ran 1 ns MD simulations for 1137 selected on small compounds. Based on their average MM/GBSA scores, 18 ligands were selected for 50 ns MD simulations along with one highly potent USP7 inhibitor used as a positive control. The in vitro enzymatic inhibition assay testing of our lead 18 molecules confirmed that 7 of these molecules were successful in USP7 inhibition. Screening results showed that within the used screening approaches, the most successful one was structure-based pharmacophore modeling with the success rate of 75 %. The identification of potent and safe USP7 small molecules as potential inhibitors is a step closer to finding appropriate effective therapies for cancer. Our lead ligands can be used as a scaffold for further structural optimization and development, enabling further research in this promising field.
    MeSH term(s) Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Molecular Dynamics Simulation ; Molecular Structure ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Structure-Activity Relationship ; Ubiquitin-Specific Peptidase 7/antagonists & inhibitors ; Ubiquitin-Specific Peptidase 7/metabolism
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Small Molecule Libraries ; USP7 protein, human (EC 3.4.19.12) ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12)
    Language English
    Publishing date 2020-11-12
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.202000675
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6280: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
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  4. Article ; Online: Targeting the NF-κB/IκBα complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models.

    Kanan, Tarek / Kanan, Duaa / Erol, Ismail / Yazdi, Samira / Stein, Matthias / Durdagi, Serdar

    Journal of molecular graphics & modelling

    2018  Volume 86, Page(s) 264–277

    Abstract: Nuclear factor-κB (NF-κB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its ... ...

    Abstract Nuclear factor-κB (NF-κB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF-κB (p50/p65) heterodimer complex in association with NF-κB inhibitor IκBα to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (∼2 million) and the Schrodinger's medically relevant Glide fragments library (∼670) were used to create the e-pharmacophore models at the potential binding site which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top-85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (∼260000 drug-like molecules) and 85 known NF-κB inhibitors were additionally screened against the derived e-pharmacophore models. The top-1000 high-scored molecules, which were well aligned to the e-pharmacophore models, from the Otava small molecule library, were then docked into the binding pocket. Finally, the selected 88 hit molecules and the 85 known inhibitors were analyzed by the MetaCore/MetaDrug™ platform, which uses developed binary QSAR models for therapeutic activity prediction as well as pharmacokinetic and toxicity profile predictions of screening molecules. Ligand selection criteria led to the refinement of 3 potent hit molecules using molecular dynamics (MD) simulations to better investigate their structural and dynamical profiles. The selected hit molecules had a low toxicity and a significant therapeutic potential for heart failure, antiviral activity, asthma and depression, all conditions in which NF-κB plays a critical role. These hit ligands were also structurally stable at the NF-κB/IκBα complex as per the MD simulations and MM/GBSA analysis. Two of these ligands (Otava IDs: 1426436 and 6248112) showed stronger binding and therefore are hypothesized to be more potent. The identification of new potent NF-κB/IκBα inhibitors may thus present a novel therapy for inflammation-mediated conditions as well as cancer, facilitating more efficient research, and leading the way to future drug development efforts.
    MeSH term(s) Binding Sites ; Computational Biology ; Drug Design ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; NF-KappaB Inhibitor alpha/chemistry ; NF-KappaB Inhibitor alpha/metabolism ; NF-kappa B/chemistry ; NF-kappa B/metabolism ; Protein Binding ; Protein Conformation ; Quantitative Structure-Activity Relationship
    Chemical Substances Ligands ; NF-kappa B ; NF-KappaB Inhibitor alpha (139874-52-5)
    Language English
    Publishing date 2018-10-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1396450-1
    ISSN 1873-4243 ; 1093-3263
    ISSN (online) 1873-4243
    ISSN 1093-3263
    DOI 10.1016/j.jmgm.2018.09.014
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3491: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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