Noor Atatreh

ERK5, a member of the MAP kinase family, has been implicated in several cancer types due to its role in regulating cell proliferation, survival, and migration. In this study, structure-based virtual screening was employed, followed by cell assays, and molecular dynamics simulations to identify novel ERK5 inhibitors. A commercially available library of 1.6 million compounds was subjected to a three-stage docking process (HTVS, SP, and XP), using the docking module in Schrodinger Maestro, yielding 40 candidates with superior docking scores compared to the co-crystallized ligand. These compounds were then tested for antiproliferative activity using an MTT assay in A549 and H292 lung cancer cell lines. Among the hits, STK038175, STK300222, and GR04 showed significant activity with IC₅₀ values of ranging from 10 to 25 µM. Western blot analysis revealed that STK300222 at 50 µM reduced the phosphorylation of ERK5 downstream targets similarly to a known inhibitor, while wound healing assays confirmed a dose-dependent decrease in cell migration. Molecular dynamics simulations of 200 ns further demonstrated that all three compounds form stable complexes with ERK5 that are comparable to the co-crystallized ligand in 5BYZ. The MD simulations also revealed strong electrostatic and solvation interactions observed for STK300222 and GR04 particularly. Furthermore, by calculating the MM-GB/SA scores from the MD trajectories, the binding affinities of the three hits, along with the co-crystallized ligand in 5BYZ, were re-scored. Although the co-crystallized ligand had the highest MM-GB/SA score at −38.96 Kcal mol⁻¹, STK300222 had a comparable score of −35.45 Kcal mol⁻¹. These results highlight STK300222 and GR04 as promising candidates for further optimization and in vivo validation as ERK5 inhibitors.

The need for new antibiotics has become a major worldwide challenge as bacterial strains keep developing resistance to the existing drugs at an alarming rate. Enoyl-acyl carrier protein reductases (FabI) play a crucial role in lipids and fatty acid biosynthesis, which are essential for the integrity of the bacterial cell membrane. Our study aimed to discover small FabI inhibitors in continuation to our previously found hit MN02. The process was initially started by conducting a similarity search to the NCI ligand database using MN02 as a query. Accordingly, ten compounds were chosen for the computational assessment and antimicrobial testing. Most of the compounds showed an antibacterial activity against Gram-positive strains, while RK10 exhibited broad-spectrum activity against both Gram-positive and Gram-negative bacteria. All tested compounds were then docked into the saFabI active site followed by 100 ns MD simulations (Molecular Dynamics) and MM-GBSA (Molecular Mechanics with Generalised Born and Surface Area Solvation) calculations in order to understand their fitting and estimate their binding energies. Interestingly, and in line with the experimental data, RK10 was able to exhibit the best fitting with the target catalytic pocket. To sum up, RK10 is a small compound with leadlike characteristics that can indeed act as a promising candidate for the future development of broad-spectrum antibacterial agents.

Patients infected with coronavirus have new experiences and hence new needs from the healthcare sector. Acknowledging patients’ experiences can exhibit promising outcomes in coronavirus management. Pharmacists are considered a vital pillar in managing patients’ experiences during their infection. A cross-sectional study was conducted to assess the experiences of COVID-19-infected individuals and the roles of pharmacists in the United Arab Emirates. The survey was face- and content-validated after being developed. Three sections were included in the survey (demographics, experiences of infected individuals, and the roles of pharmacists). Data were analyzed using the Statistical Package for the Social Sciences. The study participants (n = 509) had a mean age of 34.50 (SD = 11.93). The most reported symptoms among participants were fatigue (81.5%), fever (76.8%), headache (76.6%), dry cough (74.1%), muscle or joint pain (70.7%), and sore throat (68.6%). Vitamin C was the most used supplement (88.6%), followed by pain relievers (78.2%). Female gender was the only factor associated with symptom severity. About 79.0% agreed that the pharmacist played an important and effective role during their infection. The most reported symptom was fatigue, with females reporting more severe symptoms. The role of the pharmacist proved to be vital during this pandemic.

Background: Patients’ adherence to medication can be assessed by several subjective or objective methods. The Global Initiative for Asthma (GINA) has recommended the use of both measures simultaneously. Objective: To assess patients’ adherence to medication using a subjective or an objective method separately, and via using a combination of both methods. As well as identifying the degree of agreement between the two methods. Methods: Participants who met the study inclusion criteria completed the Adherence to Asthma Medication Questionnaire (AAMQ). A retrospective audit was conducted in order to extract pharmacy refill records for the previous twelve months. The patients’ pharmacy refill records were expressed using the Medication Possession Ratio (MPR). Data were analyzed using the Statistical Package for Social Science. The degree of agreement was determined by Cohen’s kappa coefficient (κ). Results: In terms of the difference in the ability of each method to identify non-adherent patients, a higher percentage of non-adherent patients were identified using the self-reported AAMQ (61.4%) compared to the pharmacy refill records (34.3%). When both methods, in combination, were used to assess adherence, the percentage of non-adherent patients was 80.0%, which is higher than each method when used separately. Twenty percent of the patients were considered adherent on both assessment methods, while 15.7% were considered non-adherent via both methods. Consequently, the AAMQ and pharmacy refill records agreed on 35.7% of the patients. The degree of agreement analysis showed a low correlation between the two methods. Conclusion: The combination strategy resulted in a higher percentage of non-adherent patients, compared to using a subjective (the AAMQ) or an objective (the pharmacy refill records) method. The GINA guideline proposition may be supported by the present study’s findings. Pharmacy Practice is a free full-text journal with a scope on the practice of pharmacy. Pharmacy Practice covers pharmaceutical care, social pharmacy, pharmacy education, process and outcome research, health promotion and education, health informatics, pharmacoepidemiology

The main protease enzyme (M^pro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the M^pro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with K_i values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.

The current pandemic caused by the COVID-19 disease has reached everywhere in the world and has affected every aspect of our lives. As of the current data, the World Health Organization (WHO) has reported more than 300 million confirmed COVID-19 cases worldwide and more than 5 million deaths. M^pro is an enzyme that plays a key role in the life cycle of the SARS-CoV-2 virus, and it is vital for the disease progression. The M^pro enzyme seems to have several allosteric sites that can hinder the enzyme catalytic activity. Furthermore, some of these allosteric sites are located at or nearby the dimerization interface which is essential for the overall M^pro activity. In this review paper, we investigate the potential of the M^pro allosteric site to act as a drug target, especially since they interestingly appear to be resistant to mutation. The work is illustrated through three subsequent sections: First, the two main categories of M^pro allosteric sites have been explained and discussed. Second, a total of six pockets have been studied and evaluated for their druggability and cavity characteristics. Third, the experimental and computational attempts for the discovery of new allosteric inhibitors have been illustrated and discussed. To sum up, this review paper gives a detailed insight into the feasibility of developing new M^pro inhibitors to act as a potential treatment for the COVID-19 disease. Graphical Abstract:

Despite available treatments, breast cancer is the leading cause of cancer-related death. Knowing that the tyrosine phosphatase SHP2 is a regulator in tumorigenesis, developing inhibitors of SHP2 in breast cells is crucial. Our study investigated the effects of new compounds, purchased from NSC, on the phosphatase activity of SHP2 and the modulation of breast cancer cell lines’ proliferation and viability. A combined ligand-based and structure-based virtual screening protocol was validated, then performed, against SHP2 active site. Top ranked compounds were tested via SHP2 enzymatic assay, followed by measuring IC50 values. Subsequently, hits were tested for their anti-breast cancer viability and proliferative activity. Our experiments identified three compounds 13030, 24198, and 57774 as SHP2 inhibitors, with IC50 values in micromolar levels and considerable selectivity over the analogous enzyme SHP1. Long MD simulations of 500 ns showed a very promising binding mode in the SHP2 catalytic pocket. Furthermore, these compounds significantly reduced MCF-7 breast cancer cells’ proliferation and viability. Interestingly, two of our hits can have acridine or phenoxazine cyclic system known to intercalate in ds DNA. Therefore, our novel approach led to the discovery of SHP2 inhibitors, which could act as a starting point in the future for clinically useful anticancer agents.

This work demonstrates synthetic strategies for the incorporation of a synthesized pyrimidine glucagon-like peptide-1 (GLP-1) agonist into alginate-coated ZIF-8. The prepared pyrimidine GLP-1 agonist used for the treatment of diabetes type II, was trapped inside polymer coated ZIF-8. The encapsulation of the GLP-1 agonist was confirmed by UV-visible and FT-IR spectroscopies. Furthermore, the release kinetics of GLP-1 agonist drug from alginate-coated ZIF-8 were investigated in phosphate-buffered saline at 37 °C at pH 8 and 1.5. The alginate-coated ZIF-8 exhibited much faster drug release at basic pH than at pH 1.5, indicating the potential of the alginate-coated ZIF-8 system to overcome the fast degradation at acidic pH of the stomach and improve the drug’s activity. This study may open the way for the synthesis of new metal organic frameworks (MOFs) to enhance drug delivery systems.

The need for new antibacterial agents is increasingly becoming of great importance as bacterial resistance to current drugs is quickly spreading. Enoyl‐acyl carrier protein reductases (FabI) are important enzymes for fatty acid biosynthesis in bacteria and other micro‐organisms. In this project, we conducted structure‐based virtual screening against the FabI enzyme, and accordingly, 37 compounds were selected for experimental testing. Interestingly, five compounds were able to demonstrate antimicrobial effect with variable inhibition activity against various strains of bacteria and fungi. Minimum inhibitory concentrations of the active compounds were determined and showed to be in low to medium micromolar range. Subsequently, enzyme inhibition assay was carried out for our five antimicrobial hits to confirm their biological target and determine their IC₅₀ values. Three of these tested compounds exhibited inhibition activity for the FabI enzyme where our best hit MN02 had an IC₅₀ value of 7.8 μM. Furthermore, MN02 is a small bisphenolic compound that is predicted to have all required features to firmly bind with the target enzyme. To sum up, hits discovered in this work can act as a good starting point for the future development of new and potent antimicrobial agents.

Background: The tumor suppressor protein p53 plays an important role in preventing tumor formation and progression through its involvement in cell division control and initiation of apoptosis. Mdm2 protein controls the activity of p53 protein through working as ubiquitin E3 ligase promoting p53 degradation through the proteasome degradation pathway. Inhibitors for Mdm2-p53 interaction have restored the activity of p53 protein and induced cancer fighting properties in the cell. Purpose: The objective of this study is to use computer-aided drug discovery techniques to search for new Mdm2-p53 interaction inhibitors. Methods: A set of pharmacophoric features were created based on a standard Mdm2 inhibitor and this was used to screen a commercial drug-like ligand library; then potential inhibitors were docked and ranked in a multi-step protocol using GLIDE. Top ranked ligands from docking were evaluated for their inhibition activity of Mdm2-p53 interaction using ELISA testing. Results: Several compounds showed inhibition activity at the submicromolar level, which is comparable to the standard inhibitor Nutlin-3a. Furthermore, the discovered inhibitors were evaluated for their anticancer activities against different breast cancer cell lines, and they showed an interesting inhibition pattern. Conclusion: The reported inhibitors can represent a starting point for further SAR studies in the future and can help in the discovery of new anticancer agents.