Breaking the energy chain: importance of ATP synthase in and its potential as a drug target.

Unveiling novel pathways for drug discovery forms the foundation of a new era in the combat against tuberculosis. The discovery of a novel drug, bedaquiline, targeting mycobacterial ATP synthase highlighted the targetability of the energy metabolism pathway. The significant potency of bedaquiline against heterogeneous population of marks ATP synthase as an important complex of the electron transport chain.

In-hospital new-onset seizures in patients admitted to the medical intensive care unit: An observational study and algorithmic approach.

Background: Seizures are one of the most common neurological complications encountered in the intensive care unit (ICU). They can occur in the background of exacerbation of a known neurological disease or secondary to non-neurological conditions such as sepsis and metabolic disturbances. However, there is a paucity of literature on the incidence and pattern of new-onset seizures in ICUs.

A Covalent Chemical Probe for nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

RA-0003022 () was identified as a high-quality covalent chemical probe for nsP2 cysteine protease (nsP2pro). Isoxazole covalently captured the active site C478 and inactivated the enzyme with a / ratio of 6000 Ms. A negative control analog RA-0025453 () retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition.

Elucidating the protective role of manganese seed priming in mitigating lead-induced oxidative stress: enhancements in growth, grain yield, and antioxidant activities of wheat.

Lead (Pb) is known to be extremely toxic to plants and awfully affects growth and productivity by interacting with morphological, biochemical, and physiological processes. Micronutrients are considered to reduce ion toxicity and modify various physiological processes involved in oxidative stress tolerance in plants. Hence, the limited literature about the application of micronutrients, particularly manganese (Mn), under lead stress thus demands more investigations.

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays.

Molybdenum Complex-Catalyzed -Alkylation of Bulky Primary and Secondary Amines.

Aliphatic allylic amines are present in a large number of complex and pharmaceutically relevant molecules. The direct amination of allylic electrophiles serves as the most common method toward the preparation of these motifs. However, the use of feedstock reaction components (allyl alcohol and aliphatic amine) in these transformations remains a great challenge.

Moderating effect of sleep quality in the relationship between coping and distress among medical students.

Introduction: The present study examined the moderating effects of sleep quality in the relationship between coping and distress among medical college students. Present study was conducted to ensure the mental health of medical students and to dig out the reasons behind their disturbed health which can directly impact their performance at work.

Methods: The study utilized a cross-sectional survey and was distributed to students at various medical institutions in the Punjab province of Pakistan from October 2019 to June 2020.

Evaluation of antibiotic utilization pattern and economic outcomes associated with surgical site infection in surgical department of tertiary care hospitals Karachi, Pakistan.

Surgical Site Infection (SSI) has an enormous impact on patients' quality of life. SSIs further stresses on allocation of different health care resources and contribute significantly in terms of high cost of care. This was a prospective study carried out in tertiary care hospitals of Karachi, Pakistan, involving abdominal surgeries and few other surgeries, in patients having 20 years of age and above, were admitted from June 2016 to May 2017.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Antialphavirus Activity.

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of (CHIKV) nsP2 protease and viral replication.

Unveiling the Bioactive Efficacy of 'Stricta' Essential Oil: Composition, In Vitro Activities, and In Silico Analyses.

Prior studies have extensively investigated the essential oil derived from the Mediterranean cypress, . However, the 'Stricta' variety, known for its ornamental value, has received less attention in terms of its oil composition and potential health benefits. The objective of this research was to comprehensively analyze the chemical components and medicinal properties of the essential oil extracted from 'Stricta' (CSSLEO) grown in Egypt.

New Glycotoxin Inhibitor from Mitigates Symptoms of Insulin Resistance and Diabetes by Suppressing AGE-RAGE Axis in Skeletal Muscle.

The current study intended to investigate the role of new natural compounds derived from the plant in mitigating symptoms of diabetes and insulin resistance in the diabetic mice model. Anti-advanced glycation activity, insulin, and adiponectin were quantified by enzyme-linked immunosorbent assay (ELISA). Glucose uptake was performed using enzymatic fluorescence assay, and glycogen synthesis was measured using PAS staining.

Effect of disease activity on the clinical outcome of SARS CoV-2 in patients with underlying rheumatic diseases; data from global rheumatology alliance.

Objectives: To determine the effect of disease activity on clinical outcomes of coronavirus disease-2019 in patients with rheumatic diseases.

Methods: The prospective, cohort study was conducted from January 1st to June 30th, 2021, at Rheumatology department, Fauji Foundation Hospital, Rawalpindi. It comprised patients of rheumatic disorders who were affected by coronavirus disease-2019.

Synthesis of high-performance antibacterial agent based on incorporated vancomycin into MOF-modified lignin nanocomposites.

The alarming rise in antibiotic resistance necessitates urgent action, particularly against the backdrop of resistant bacteria evolving to render conventional antibiotics less effective, leading to an increase in morbidity, mortality, and healthcare costs. Vancomycin-loaded Metal-Organic Framework (MOF) nanocomposites have emerged as a promising strategy in enhancing the eradication of pathogenic bacteria. This study introduces lignin as a novel synergistic agent in Vancomycin-loaded MOF (Lig-Van-MOF), which substantially enhances the antibacterial activity against drug-resistant bacteria.

Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.

We herewith applied a generic hit identification method (POEM) for difficult targets of known three-dimensional structure, relying on the simple knowledge of physicochemical and topological properties of a user-selected cavity. Searching for local similarity to a set of fragment-bound protein microenvironments of known structure, a point cloud registration algorithm is first applied to align known subpockets to the target cavity. The resulting alignment then permits us to directly pose the corresponding seed fragments in a target cavity space not typically amenable to classical docking approaches.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Anti-alphavirus Activity.

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication.

Unraveling the contribution of copper seed priming in enhancing chromium tolerance in wheat by improving germination, growth, and grain yield.

Exposure to chromium (Cr) on farmlands drastically restricts the growth and productivity of cereal crops, including wheat (Triticum aestivum L.). Utilizing micronutrients, the seed-priming strategy is crucial to preventing the adverse consequences of Cr-stress.

Numerical Approximation of a Nonequilibrium Model of Gradient Elution Chromatography Considering Different Functional Relationships between Model Parameters and Solvent Composition.

In this paper, a rigorous theoretical study is conducted to analyze the influence of varying solvent compositions on the retention characteristics of elution profiles within a fixed-bed liquid chromatographic column. In gradient chromatography, the propagation speed of elution profiles is manipulated through a progressive variation in the mobile-phase composition. Consequently, enhanced separation of the mixture components can be achieved together with a reduction in the requisite recycling times for subsequent injections.

Development of Peptide Displacement Assays to Screen for Antagonists of DDB1 Interactions.

The DNA damage binding protein 1 (DDB1) is an essential component of protein complexes involved in DNA damage repair and the ubiquitin-proteasome system (UPS) for protein degradation. As an adaptor protein specific to Cullin-RING E3 ligases, DDB1 binds different receptors that poise protein substrates for ubiquitination and subsequent degradation by the 26S proteasome. Examples of DDB1-binding protein receptors are Cereblon (CRBN) and the WD-repeat containing DB1- and UL4-ssociated actors (DCAFs).

Development and characterisation of buccal dispersible film, syrup and effervescent granules of extemporaneous antigout remedy.

Homemade medicinal remedies used to treat both acute and chronic ailments for centuries need to be transformed into modern evidence-based dosage forms. Therefore, the present study aimed to develop buccal dispersible film, syrup and effervescent granules of an extemporaneous antigout homemade remedy. The dosage forms were prepared using holistic remedy (HR) as an active entity and excipients masking disagreeable features.