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 of the target 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 additional 85 known NF κB inhibitors were 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) were energetically more favorable and therefore are hypothesized to be more potent. Identifying 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.
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 relationship (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. Only 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamic (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.
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.
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 v 3.87 ± 0.81) and treatment modalities (2.54 ± 0.96 v 3.79 ± 0.88), P < .001. Students believed the program was beneficial, felt more confident in applying their knowledge in the clinic and in delivering bad news, and were more interested in pursuing oncology-related fields, P < .001. 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.
11024 Background: Undergraduate medical education in oncology is often fragmented and non-standardized among medical schools (BMC Med Educ 17:100, 2017). Oncology education initiatives are thus critically needed to increase cancer awareness and improve medical students’ understanding of the principles and multidisciplinary approach of oncology. We designed and implemented an online education program with the aim of providing medical students with an early exposure to the field of oncology. Our program was adapted from the Australian Ideal Oncology Curriculum for Medical Schools and included six sessions covering the basics of cancer biology, prevention and screening, diagnosis and patient management, principles of treatment modalities, principles of surgical oncology, as well as counselling and communications skills. Methods: Medical students at our institution were invited to participate. We also invited medical students from other faculties via the support of student groups namely the nation’s medical student union and our ASCO Oncology Student Interest Group (OSIG). Invitations were sent by email and/or via social media along with a brochure outlining the conference’s program and instructions to use the Zoom platform. Students were asked to voluntarily fill online pre- and post-conference anonymous surveys. Students self-assessed their competency, personal attributes, future career aspirations, and provided an evaluation of the program. A five-point Likert scale was used for most questions, in which 1 indicated strong disagreement and 5 indicated strong agreement with the statement. Results: Nearly 300 students from over 50 medical schools in Turkey attended the live program. Only students (n = 228) who completed both the pre- and post-conference surveys were included in our study. ASCO OSIG members made up 24.1% (n = 55) of the students. Among the participants, 73.7% (n = 168) were preclinical students (years 1-3) and 26.3% (n = 60) were clinical students (years 4-6). Students’ overall self-reported rating of their knowledge significantly improved in each of the six sessions, with the greatest pre-post difference observed for diagnosis and patient management (2.51 ± 1 vs 3.87 ± 0.81) followed by principles of treatment modalities (2.54 ± 0.96 vs 3.79 ± 0.88), P < 0.001. Most students believed the program was beneficial in improving their current understanding of oncology with a mean of 4.43 ± 0.76. Most students (92.5%) were “likely” or “very likely” to recommend the program to their colleagues. Conclusions: Students’ evaluation of the online oncology program demonstrated significant benefit and knowledge improvement. Our successfully piloted teaching model of oncology for medical students can be adapted and implemented at medical schools globally. Further development and continuation of our educational initiative is undergoing.
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