Sestrin2 (SESN2) is a highly conserved stress-inducible protein that serves as a central hub for integrating cellular responses to nutrient availability, oxidative stress, and endoplasmic reticulum (ER) stress. A key function of SESN2 is its role as a direct sensor for the branched-chain amino acid (BCAA) leucine, which modulates the activity of the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth and metabolism. While the functional link between leucine and SESN2 is well-established, the precise molecular determinants that confer its high specificity for leucine over other BCAAs, such as isoleucine and valine, remain poorly understood. This study employs an integrated computational approach, spanning atomic interactions to global protein dynamics, combining molecular docking, extensive all-atom molecular dynamics (MD) simulations, and binding free energy calculations, to elucidate the structural and dynamic basis of BCAA-SESN2 recognition. Our thermodynamic analysis reveals a distinct binding affinity hierarchy (Leucine > Isoleucine > Valine), which is primarily driven by superior van der Waals interactions and the shape complementarity of leucine’s isobutyl side chain within the protein’s hydrophobic pocket. Critically, a quantitative analysis of the conformational ensemble reveals that leucine induces a dramatic collapse of the protein’s structural heterogeneity. This “conformational locking” mechanism funnels the flexible, high-entropy unbound protein—which samples 35 distinct conformations—into a sharply restricted ensemble of just 9 stable states. This four-fold reduction in conformational freedom is accompanied by a kinetic trapping effect, which significantly lowers the rate of transitions between states. This process of conformational selection stabilizes a well-defined, signaling-competent structure, providing a comprehensive, atom-to-global-scale model of SESN2’s function. In the context of these findings, this work provides a critical framework for understanding SESN2’s complex role in disease and offers a clear rationale for the design of next-generation allosteric therapeutics.

Triple-negative breast cancer (TNBC) is the most clinically aggressive subtype of breast cancer, characterized by the absence of targetable hormone receptors and HER2 amplification, significantly constraining treatment choices. Estrogen Receptor Beta (ERβ) has emerged as a biologically relevant yet underutilized target in TNBC, with its re-expression linked to tumor suppression and improved prognosis, prompting the development of selective ERβ modulators as a precision therapeutic approach. We introduce ERβ-Score, an interpretable machine learning scoring system developed using a curated dataset of 1699 ERβ bioactive chemicals obtained from ChEMBL, characterized by 39 physicochemical and three-dimensional molecular descriptors. After implementing scaffold-disjoint train/test partitioning to avert structural data leakage, a Gradient Boosting Classifier, fine-tuned through Bayesian hyperparameter optimization, attained in five-fold cross-validation a Precision–Recall AUC (Area Under the Curve) of 0.891, a ROC-AUC (Receiver Operating Characteristic) of 0.888, a Matthews Correlation Coefficient of 0.664, an F1-score of 0.838, and a balanced accuracy of 0.831; on the scaffold-disjoint hold-out test set it attained a Precision–Recall AUC of 0.905, a ROC-AUC of 0.864, and a Matthews Correlation Coefficient of 0.578, indicating strong and balanced discrimination between active and inactive ERβ modulators. We note explicitly that this scaffold-disjoint hold-out constitutes internal validation, since it derives from the same curated ChEMBL workflow used for model development, and it is therefore reported throughout as scaffold-disjoint internal validation rather than as independent external validation. The applicability domain boundaries were established using a k-nearest-neighbor Tanimoto-similarity method with ECFP4 (Extended-Connectivity Fingerprint with a Diameter of 4) fingerprints, offering a quantitative confidence metric that identifies structurally new molecules beyond the model’s reliable prediction range. External validation against independent Tox21 ERβ bioassay data confirmed genuine, statistically significant predictive signal (ROC-AUC = 0.71) while revealing reduced sensitivity for structurally novel active compounds. The model was subsequently used for extensive virtual screening of natural product and drug-like compound libraries, with prioritized candidates undergoing structure-based molecular docking against the ERβ co-crystal structure (PDB: 7XWQ) using Smina, facilitating a comprehensive evaluation of hits based on both ligand and structural properties. To enhance accessibility, the complete pipeline was implemented as an open-access interactive web application utilizing Streamlit, enabling researchers to input any SMILES string and obtain, in real time, an activity prediction with a probability score, applicability domain classification, Lipinski drug-likeness assessment, interactive three-dimensional visualization of protein–ligand interactions, and on-demand docking within the ERβ active site.

Aims: To quantify prescribing adherence to renal dosing recommendations in adults with chronic kidney disease (CKD; Stage 3 and above) and to evaluate the clinical consequences of non‐adherence. Methods: This systematic review and meta‐analysis was conducted in accordance with PRISMA 2020 guidelines and registered in PROSPERO (CRD42025620883). Eight electronic databases were searched from inception to 31 December 2025. Quantitative studies assessing renal dose adjustment practices in adults with advanced CKD were included in the review. Two reviewers independently performed study selection, data extraction and quality assessment. Random‐effects meta‐analyses (REML) were used to pool adherence proportions at prescription/order and patient levels. Results: Thirty studies were included in the review. The observational studies were of moderate to high quality, while the two interventional studies had moderate risk of bias due to confounding. Prescribing adherence to renal dosing guidelines ranged from 33% to 87.7%. Pooled prescription/order‐level guideline adherence ( n = 16) was 0.48 (95% CI 0.42–0.55; I ² ≈ 98%). Conversely, the pooled patient‐level guideline adherence ( n = 7) was higher at 0.7 (95% CI 0.57–0.83; I ² ≈ 99.9%). The study results suggest that the prevalence of prescribing non‐adherence to renal dosing guidelines was high and may be associated with various adverse drug events. Conclusions: The available evidence suggests that adherence to renal dosing recommendations in adults with advanced CKD is variable and may be suboptimal. The pooled estimate suggests a potential safety gap, although substantial heterogeneity limits interpretation. Furthermore, non‐adherence to renal dosing recommendations was associated with adverse clinical consequences and increased healthcare utilization. High‐quality studies are needed to inform effective strategies aimed at improving prescribing practices and medication safety.

Adverse Drug Reaction (ADR) reports using spontaneous reporting systems are known to assist in the identification of new, rare, and serious ADRs in clinical practice. Research characterizing ADRs in patients taking psychotropics in Qatar is scarce. This study aims to describe psychotropic-related ADRs’ characteristics, risk factors, severity, causality, and preventability. This is a retrospective chart review of patients within Hamad Medical Corporation’s (HMC) Mental Health Services (MHS) between 2018–2022. ADR reports submitted to the Spontaneous Reporting System database were electronically extracted and analyzed. Data on the type, frequency, onset, severity, and outcomes of adverse reactions, along with patient demographics and comorbidities, were extracted and summarized using quantitative methods. A total of 908 reports were analyzed. Most ADRs were reported in males (543, 59.83%), in the year 2020 (256, 28.2%). Most reactions were categorized as “moderate” (67.7%), followed by “mild” reactions (30.9%). Extrapyramidal symptoms (EPS) were the highest reported ADRs (46.5%) followed by gastrointestinal side effects (13.3%) and hyperprolactinemia (13.2%) with Haloperidol as the most reported offending agent. Around half of the ADRs were classified as probable and 65.0% were deemed not preventable Psychotropic polypharmacy remained a significant independent risk factor for EPS, increasing the odds of by 45% (OR = 1.45, 95% CI [1.08–1.95], p = 0.015). This is the first study to describe the characteristics of psychotropic-related ADRs reported within HMC mental health services in Qatar. Most ADRs were moderate in severity with EPS being the most common ADR and haloperidol as the most reported suspected offending agent. Patterns discovered in this study can aid in enhancing patient safety through educating health care providers on predicting and minimizing preventable ADRs.

Aims To quantify adherence to renal dosing recommendations in adults with advanced chronic kidney disease (CKD; stages 3–5, including dialysis) and to evaluate the clinical consequences of non-adherence. Methods This systematic review and meta-analysis was conducted in accordance with PRISMA 2020 and registered in PROSPERO (CRD42025620883). Eight electronic databases were searched from inception to 31 December 2025. Quantitative studies assessing renal dose adjustment practices in adults with advanced CKD were included. Two reviewers independently performed study selection, data extraction, and quality assessment using the Newcastle–Ottawa Scale and ROBINS-I. Random-effects meta-analyses (REML) were used to pool adherence proportions at prescription/order and patient levels. Results Thirty studies were included. Observational studies were of moderate to high quality (NOS 6–9/9), while two interventional studies had moderate risk of bias due to confounding. Adherence ranged from 33% to 83%. Pooled prescription/order-level adherence (n=16) was 48% (95% CI 0.42–0.55; I ² ≈98%). Patient-level adherence (n=7) was higher at 70% (95% CI 0.57–0.83; I ² ≈99.9%). Non-adherence was associated with adverse drug events, including hypoglycemia and nephrotoxicity, and with increased emergency department visits, hospitalizations, and mortality. Conclusions Adherence to renal dosing recommendations in advanced CKD is suboptimal and highly variable across settings. Interventions targeting prescribing systems, including clinical decision support tools, are warranted to improve guideline adherence and medication safety in this high-risk population.