Discovery of novel natural products as dual MNK/PIM inhibitors for acute myeloid leukemia treatment: Pharmacophore modeling, molecular docking, and molecular dynamics studies

MNK-2 and PIM-2 kinases play an indispensable role in cell proliferation signaling pathways linked to tyrosine kinase inhibitors resistance. In this study, pharmacophore modeling studies have been conducted on the co-crystalized ligands of MNK-2 and PIM-2 enzyme crystal structures to determine the essential features required for the identification of potential dual inhibitors. The obtained pharmacophore features were then screened against a library of 270,540 natural products from the ZINC database. The matched natural molecules were docked into the binding sites of MNK-2 and PIM-2 enzymes. The compounds with high docking scores with the two enzymes were further subjected to MM-GBSA calculations and ADME prediction. This led to the identification of compound 1 (ZINC000085569211), compound 2 (ZINC000085569178), and compound 3 (ZINC000085569190), with better docking scores compared to the reference co-crystallized ligands of MNK-2 and PIM-2. Moreover, compounds 1‒3 displayed better MM-GBSA binding free energies compared to the reference ligands. Finally, molecular dynamics (MD) study was used to assess the interaction stability of the compounds with MNK-2. To this end, compounds 1 and 3 bound strongly to the target during the whole period of MD simulation. The findings of the current study may further help the researchers in the discovery of novel molecules against MNK-2 and PIM-2

Assessing suboptimal health status in the Saudi population: Translation and validation of the SHSQ-25 questionnaire

Background: Suboptimal Health Status (SHS) is realised as a vital feature for improving global health. However, the Arabian world does not have a validated instrument for screening SHS in their population. Therefore, the study aimed to evaluate the psychometric properties of Arabic-translated SHS (ASHSQ-25) in the Saudi Arabian population. Methods: We conducted a cross-sectional study among the conveniently sampled 1590 participants from the Saudi population (with a 97.4% response rate). The data was gathered through an online survey and then exported into SPSS and AMOS version 26.0 for analysis. Mann-Whitney and Kruskal-Wallis tests were used to identify the median difference between demographic groups. The one-tailed 90% upper limit of SHS scores was chosen as the cut-off criteria for SHS. Reliability and confirmatory analysis were performed for the psychometric evaluation of ASHSQ-25 in the Saudi Arabian context. Results: This study demonstrates that the ASHSQ-25 has good internal consistency, interclass correlation coefficient (ICC) = 0.92; 95% confidence interval (CI) = 0.91-0.93) and reliability (Cronbach\u27s α = 0.92). The confirmatory factor analysis (CFA) results indicated a good fit of the databased on the CMIN/degrees of freedom (df) = 4.461, comparative fit index (CFI) = 0.94, Tucker Lewis index (TLI) = 0.93, and Root Mean Square Error of Approximation (RMSEA) = 0.05. The result factor loadings for each item were high ( ≥ 0.55), except for one item from the immune system subscale. The SHS cut-off point for ASHSQ-25 was 33, leading to a 23.7% prevalence of SHS. Conclusions: This study reveals that ASHSQ-25 has appropriate internal consistency and structural validity to assess SHS in an Arabic-speaking population; therefore, it is recommended

Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies

Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its overexpression and activation in various cancers render it a potential candidate for the development of targeted therapeutics. While several known Pin1 inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, the pursuit of novel Pin1 inhibitors has gained considerable attention in the field of medicinal chemistry. In this study, we employed the Phase tool from Schrödinger to construct a structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) from the SN3 database underwent screening to identify compounds sharing pharmacophoric features with the native ligand. This resulted in 650 compounds, which then underwent molecular docking and binding free energy calculations. Among them, SN0021307, SN0449787 and SN0079231 showed better docking scores with values of −9.891, −7.579 and −7.097 kcal/mol, respectively than the reference compound (−6.064 kcal/mol). Also, SN0021307, SN0449787 and SN0079231 exhibited lower free binding energies (−57.12, −49.81 and −46.05 kcal/mol, respectively) than the reference ligand (−37.75 kcal/mol). Based on these studies, SN0021307, SN0449787, and SN0079231 showed better binding affinity that the reference compound. Further the validation of these findings, molecular dynamics simulations confirmed the stability of the ligand-receptor complex for 100 ns with RMSD ranging from 0.6 to 1.8 Å. Based on these promising results, these three phytochemicals emerge as promising lead compounds warranting comprehensive biological screening in future investigations. These compounds hold great potential for further exploration regarding their efficacy and safety as Pin1 inhibitors, which could usher in new avenues for combating cancer

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (−11.569 to −7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of −10.643 and −10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of −67.96 and −50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery

Cognitive Flexibility’s Role in Reducing Academic Stress During the COVID-19 Pandemic

Background: Cognitive flexibility (CF) in the psychological literature has been described as an individual’s ability to produce several solutions and retain control in novel situations. Recently, the COVID-19 pandemic appeared to be an ideal scenario that demanded the application of adaptive thinking by students to deal with several challenges of the pandemic. Aim: This study aimed to assess the role of CF in reducing academic stress among university students due to the sudden and strict implementation of online education during the COVID-19 pandemic. Methods: This study employed a cross-sectional survey design and data collection was completed during the 2020– 2021 academic year. The study sample comprised 328 university students from Saudi Arabia. The online survey method was used, and study tools comprises of reliable and valid psychological measures to assess CF, academic stress, the negative impact of the COVID-19 pandemic, and emotional symptoms. IBMSPSS25 was used for statistical analysis of data. Multiple regression analysis was applied to determine the role of CF in reducing academic stress after controlling for other factors such as gender, age, academic year, negative impact of COVID-19 on daily life, and unpleasant emotional experiences. Results: CF was significantly decreased the risk of experiencing academic stress (b = ‒0.196, t = ‒3.54; p Conclusion: The current findings suggest that CF could be fostered among university students as a useful mental tool to cope with academic stress during less-structured educational and social circumstances that may impact their daily lives and emotional wellness. Plain Language Summary: Cognitive Flexibility (CF), also known as the capacity for adaptive thinking, has been recognized as an important mental coping tool. The prolonged implementation of full-time online studies during the COVID-19 pandemic has been a source of academic stress among university students. This study examined the positive impact of cognitive flexibility on academic stress by collecting data from university students who underwent full-time online studies during the COVID-19 pandemic in Saudi Arabia. The study findings validated the protective role of CF, and recommended devising appropriate educational strategies that could foster adaptive thinking and enable students to cope with study-related stressors during uncertain times.</p

Cognitive Flexibility’s Role in Reducing Academic Stress During the COVID-19 Pandemic

Background: Cognitive flexibility (CF) in the psychological literature has been described as an individual’s ability to produce several solutions and retain control in novel situations. Recently, the COVID-19 pandemic appeared to be an ideal scenario that demanded the application of adaptive thinking by students to deal with several challenges of the pandemic. Aim: This study aimed to assess the role of CF in reducing academic stress among university students due to the sudden and strict implementation of online education during the COVID-19 pandemic. Methods: This study employed a cross-sectional survey design and data collection was completed during the 2020– 2021 academic year. The study sample comprised 328 university students from Saudi Arabia. The online survey method was used, and study tools comprises of reliable and valid psychological measures to assess CF, academic stress, the negative impact of the COVID-19 pandemic, and emotional symptoms. IBMSPSS25 was used for statistical analysis of data. Multiple regression analysis was applied to determine the role of CF in reducing academic stress after controlling for other factors such as gender, age, academic year, negative impact of COVID-19 on daily life, and unpleasant emotional experiences. Results: CF was significantly decreased the risk of experiencing academic stress (b = ‒0.196, t = ‒3.54; p Conclusion: The current findings suggest that CF could be fostered among university students as a useful mental tool to cope with academic stress during less-structured educational and social circumstances that may impact their daily lives and emotional wellness. Plain Language Summary: Cognitive Flexibility (CF), also known as the capacity for adaptive thinking, has been recognized as an important mental coping tool. The prolonged implementation of full-time online studies during the COVID-19 pandemic has been a source of academic stress among university students. This study examined the positive impact of cognitive flexibility on academic stress by collecting data from university students who underwent full-time online studies during the COVID-19 pandemic in Saudi Arabia. The study findings validated the protective role of CF, and recommended devising appropriate educational strategies that could foster adaptive thinking and enable students to cope with study-related stressors during uncertain times.</p

Molecular Docking and Molecular Dynamics Studies Reveal the Anticancer Potential of Medicinal-Plant-Derived Lignans as MDM2-P53 Interaction Inhibitors

The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6′-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of −7.526 kcal/mol, −7.438 kcal/mol, and −7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (−6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments