Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Integrated computational approaches for designing potent pyrimidine-based CDK9 inhibitors: 3D-QSAR, docking, and molecular dynamics simulations.

CDK9 is an emerging target for the development of anticancer drugs. The development of CDK9 inhibitors with significant potency had consistently posed a formidable challenge. In the current research, a number of computational methodologies, such as, 3D-QSAR, molecular docking, fingerprint analysis, molecular dynamic (MD) simulations followed by MMGB/PBSA and ADMET studies were used systemically to uncover the binding mechanism of pyrimidine derivatives against CDK9. The CoMFA and CoMSIA models having high q2 (0.53, 0.54) and r2 values (0.96, 0.93) respectively indicating that model could accurately predict the bioactivities of CDK9 inhibitors. Using the R-group exploration technique implemented by the Spark™ by Cresset group, the structural requirements revealed by the contour maps of model were utilized strategically to create an in-house library of 100 new CDK9 inhibitors. Additionally, the compounds from the in-house library were mapped into 3D-QSAR model which predicted pIC50 values comparable to the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to elucidate the essentials of CDK9 inhibitor design. MD simulations (100 ns) were performed on the selected docked complexes A21, A14 and D98 which contributed in validating the binding interactions. According to the findings of binding free energy analysis (MMGB/PBSA), It was observed that residues CYS106 and GLU107 had a considerable tendency to facilitate ligand-protein interactions via H-bond interactions. The aforementioned findings have the potential to enhance researchers comprehension of the mechanism underlying CDK9 inhibition and may be utilized in the development of innovative and efficacious CDK9 inhibitors.

Prescribing Patterns for Upper Respiratory Tract Infections: A Prescription-Review of Primary Care Practice in Quetta, Pakistan and the Implications.

Background: To identify and address the potential overuse of antibiotics, it is important to ascertain the prescribing practices of physicians. We, therefore, conducted this prescription analysis to document URTI-specific antibiotic prescription frequency in a public primary healthcare setting of Quetta city, Pakistan. Methods: A retrospective record review was conducted of all prescriptions for URTIs in Combined Military Hospital, Quetta from 1 March to 31st May 2021. The Mann-Whitney U and Jonckheere-Terpstra test was used to evaluate the association between the tendencies of a different group of prescribers. p-value of <0.05 was of statistical significance. Results: Over the 3 months, 50,705 prescriptions were screened and analyzed according to the established inclusion and exclusion criteria. A total of 4,126 (8.13%) URTI prescriptions met the inclusion criteria, of which 2,880 (69.80%) prescriptions contained antibiotics. Among all antibiotics, penicillins (Amoxicillin + Clavulanate) were the most prescribed antibiotic, constituting 1,323 (45.9%) of total antibiotics prescribed for all cases, followed by the Macrolide group 527 (18.2%). The Jonckheere-Terpstra test revealed a statistically significant association between the status of the prescriber and the diagnosis (p = 0.002). Furthermore, a moderate positive trend was reported with specialists being more competent in antibiotic prescribing based on their diagnosis, followed by postgraduates and house officers (τ = 0.322). Conclusion: The prescribing patterns for the management of URTIs in the hospital were inconsistent with current guidelines. Strict adherence to guidelines must be ensured and antibiotic prescribing for URTIs should be discouraged.

Spectroscopic interaction studies of H2 receptor antagonists with levocetirizine.

Patients with allergic rhinitis may also suffer abdominal pain, gastritis or peptic ulcer. In this condition patient may use levocetirizine with famotidine or ranitidine. These drugs have potential to interact with another drug and form complex. The aim of the present study is to evaluate the possible drug drug interaction with each other which may cause increase or decrease of therapeutic effects. For this purpose, validity of Beer Lambert law was checked, lone availability of famotidine (20gm), ranitidine (150gm) and levocetirizine (5mg) were studied in pH simulated to gastric juice (pH 1), pH 4, pH 7.4 and in pH 9 and finally percent availabilities of these drugs were calculated with the help of simultaneous equation. Results showed high percentage of levocetirizine in all pH as 300.32%, 514.41%, 173.38% and 220.68% in presence of famotidine but very low availability of famotidine as 5.36%, 35.38%, 51.87% and 10.89% in presence of levocetirizine. In the case of levocetirizine and ranitidine interaction, zero percent levocetirizine was available at pH 1and 9, 56.28% in pH 4 and 191.1% in pH 7.4. On the other hand, ranitidine was available as 95.36%, 127.93%, 41.47% and 144.3%. These results showed that percentage of all drugs were altered in presence of each other due to drug-drug interaction. This may be due to the charge transfer binding capabilities of the drugs which resulted in significantly changed availability of famotidine, ranitidine as well as levocetirizine.

Profile and Predictors of Maternal Quality of Life During Physiological Pregnancy: A Cross-Sectional Analysis.

BACKGROUND: Quality of Life (QoL) and its determinants are significant in all stages of life, including pregnancy. The physical and emotional changes during pregnancy affect the QoL of pregnant women, affecting both maternal and infant health. Hence, assessing the QoL of pregnant women is gaining interest in literature. We, therefore, aimed to describe the QoL of pregnant women during physiological pregnancy and to identify its associated predictors in women attending a public healthcare institute of Quetta city, Pakistan. METHODS: A cross-sectional study was conducted at the Obstetrics and Gynecology Department of Sandeman Provincial Hospital Quetta city, Pakistan. The respondents were asked to answer the Urdu (lingua franca of Pakistan) version of the Quality of Life Questionnaire for Physiological Pregnancy. Data were coded and analyzed by SPPS v 21. The Kolmogorov-Smirnov test was used to establish normality of the data and non-parametric tests were used accordingly. Quality of Life was assessed as proposed by the developers. The Chi-square test was used to identify significant associations and linear regression was used to identify the predictors of QoL. For all analyses, p < 0.05 was taken significantly. RESULTS: Four hundred and three pregnant women participated in the study with a response rate of 98%. The mean QoL score was 19.85 ± 4.89 indicating very good QoL in the current cohort. The Chi-Square analysis reported a significant association between age, education, occupation, income, marital status, and trimester. Education was reported as a positive predictor for QoL (p = 0.006, ß = 2.157). On the other hand, trimester was reported as a negative predictor of QoL (p = 0.013, ß = -1.123). CONCLUSION: Improving the QoL among pregnant women requires better identification of their difficulties and guidance. The current study highlighted educational status and trimester as the predictors of QoL in pregnant women. Health care professionals and policymakers should consider the identified factors while designing therapeutic plans and interventions for pregnant women.