High throughout drug screening

In the realm of medicinal chemistry, the primary objective is to swiftly optimize a multitude of chemical properties of a set of compounds to yield a clinical candidate poised for clinical trials. In recent years, two computational techniques, machine learning (ML) and physics-based methods, have evolved substantially and are now frequently incorporated into the medicinal chemist's toolbox to enhance the efficiency of both hit optimization and candidate design. Both computational methods come with their own set of limitations, and they are often used independently of each other...

The chemokine receptor CXCR4 is a critical target for the treatment of several cancer types and HIV-1 infections. While orthosteric and allosteric modulators have been developed targeting its extracellular or transmembrane regions, the intramembrane region of CXCR4 may also include allosteric binding sites suitable for the development of allosteric drugs. To investigate this, we apply the Gaussian Network Model (GNM) to the monomeric and dimeric forms of CXCR4 to identify residues essential for its local and global motions located in the hinge regions of the protein...

Rare human pathogens are infrequently observed clinically but can lead to undiagnosed infections, delays in treatment, severe complications, including death. Traditional diagnostic tools cannot routinely detect rare infections in public health settings. This study focuses on the incidence and outcomes of rare pathogenic microorganisms over 13 years (2010-2022) using PubMed database to obtain epidemiological data on rare bacterial, parasitic, and fungal infections in hospitals throughout India. A total of 974 articles were screened using case studies, datasets, comments, classical articles, letters, editorials, observational studies, and meta-analyses...

Alzheimer's disease (AD) is a complex neurological disorder and no effective drug is available for its treatment. Numerous pathological conditions are believed to be responsible for the initiation and development of AD including c-Jun N-terminal kinases (JNKs). The JNKs are one of the enzymes from the mitogen-activated protein kinase (MAPK) family that controls the phosphorylation of various transcription factors on serine and threonine residues, and hold significant responsibilities in tasks like gene expression, cell proliferation, differentiation, and apoptosis...

OBJECTIVE: There are substantial barriers to conducting research among individuals with stigmatized and complicated health conditions like substance use disorders. These barriers slow progress when developing, refining, and assessing interventions to better treat underserved populations. Virtual focus groups are an innovative method for collecting data from individuals via a discreet and accessible platform which can inform novel as well as existing treatment approaches. This article reports on the feasibility and acceptability of virtual focus groups as a mechanism to recruit and engage geographically and demographically diverse samples of participants with substance use disorders that are otherwise logistically difficult to assess...

Dried blood spot (DBS) technology is a simple and convenient method for collecting, transporting, and storing blood samples on filter paper, and has numerous applications in the clinical, research, and public health settings. This technique is gaining popularity in the field of forensic science because it facilitates the rapid analysis of prohibited drugs in blood samples and offers significant advantages in toxicology scenarios such as drinking-driving screening, drug abuse detection, and doping detection...

PURPOSE: Glioblastoma (GBM) is a lethal brain tumor. Standard of care treatment comprising surgery, radiation and chemotherapy results in median survival rates of 12-15 months. Molecular targeted agents identified using conventional two-dimensional (2D) in vitro models of GBM have failed to improve outcome in patients, rendering such models inadequate for therapeutic target identification. A previously developed 3D GBM in vitro model that recapitulates key GBM clinical features and responses to molecular therapies was investigated for utility for screening novel radiation-drug combinations using gold-standard clonogenic survival as readout...

Nitric oxide (NO) exhibits both pro- and anti-tumor effects. Therefore, real-time in vivo imaging and quantification of tumor NO dynamics are essential for understanding the conflicting roles of NO played in pathophysiology. The current molecular probes, however, cannot provide high-resolution imaging in deep tissues, making them unsuitable for these purposes. Herein, we designed a photoacoustic probe with an absorption maximum beyond 1000 nm for high spatial quantitative imaging of in vivo tumor NO dynamics...

Blood vessels constitute a closed pipe system distributed throughout the body, transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys. Changes in blood vessels are related to many disorders like stroke, myocardial infarction, aneurysm, and diabetes, which are important causes of death worldwide. Translational research for new approaches to disease modeling and effective treatment is needed due to the huge socio-economic burden on healthcare systems...

Ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry(UPLC-Q/TOF-MS) was employed to examine the impact of Coptidis Rhizoma(CR) and its processed products on the metabolism in the rat model of oral ulcer due to excess heat and to compare the effectiveness of CR and its three products. Male SD rats were randomly allocated to the sham-operation(Sham), model(M, oral ulcer due to excess heat), CR, wine/Zingiberis Rhizoma Recens/Euodiae Fructus processed CR(wCR/zCR/eCR), and Huanglian Shangqing Tablets(HST) groups...

Visceral Leishmaniasis (VL) has a high death rate, with 500,000 new cases and 50,000 deaths occurring annually. Despite the development of novel strategies and technologies, there is no adequate treatment for the disease. Therefore, the purpose of this study is to find structural analogs of natural products as potential novel drugs to treat VL. We selected structural analogs from natural products that have shown antileishmanial activities, and that may impede the purine salvage pathway using computer-aided drug-design (CADD) approaches...

The Quorum Sensing (QS) system in bacteria has become a focal point for researchers aiming to develop novel antimicrobials to combat multidrug-resistant bacteria. Pseudomonas aeruginosa , an opportunistic Gram-negative bacterium, has developed resistance against a variety of antimicrobial agents, making it a formidable pathogen responsible for nosocomial infections. QS system mainly controls the expression of genes responsible for biofilm formation and virulence of bacteria. Within the QS system of P. aeruginosa , the transcription activator LasR plays a pivotal role and is an appealing target for the development of antimicrobial agents...

BACKGROUND: TANK-binding kinase 1 (TBK1) is an important serine/threonine kinase involved in inflammatory signaling pathways, influencing cellular processes such as proliferation, programmed cell death, autophagy, and immune response regulation. Dysregulation of TBK1 has been linked to cancer progression and neurodegenerative disorders, making it an attractive target for therapeutic development. This study aimed to identify potential TBK1 inhibitors using a structure-based virtual screening approach...

BACKGROUND: In patients with schizophrenia, study design to optimize adherence and objective measurement of adherence is critical for interpreting results. Two randomized, double-blind studies evaluating adjunctive pimavanserin in patients with schizophrenia who received stable antipsychotic treatment included measures to encourage and assess treatment adherence. OBJECTIVE: This post hoc analysis evaluated adherence levels achieved in the Phase III ENHANCE study (NCT02970292) and the Phase II ADVANCE study (NCT02970305)...

Drug metabolism plays a crucial role in drug fate, including therapeutic inactivation or activation, as well as the formation of toxic compounds. This underscores the importance of understanding drug metabolism in drug discovery and development. Considering the substantial costs associated with traditional drug development methods, computational approaches have emerged as valuable tools for predicting the metabolic fate of drug candidates. With this in mind, the present study aimed to investigate the potential mechanisms underlying the modulation of microsomal cytochrome P450 3A1 (CYP3A1) enzyme activity by various phytochemicals found in Cichorium intybus L...

Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, nonselective cation channel with a widespread distribution throughout the body. It is involved in many pathological and physiological processes, making it a potential therapeutic target for various diseases, including Alzheimer's disease, Parkinson's disease, and cancers. New analytical techniques are beneficial for gaining a deeper understanding of its involvement in disease pathogenesis and for advancing the drug discovery for TRPM2-related diseases...

Marburg virus (MV) is a highly etiological agent of haemorrhagic fever in humans and has spread across the world. Its outbreaks caused a 23-90% human death rate. However, there are currently no authorized preventive or curative measures yet. VP40 is the MV matrix protein, which builds protein shell underneath the viral envelope and confers hallmark filamentous. VP40 alone is able to induce assembly and budding of filamentous virus-like particles (VLPs), which resemble authentic virions. As a result, this research is credited with clarifying the function of VP40 and leading to the discovery of new therapeutic targets effective in combating MV disease (MVD)...

OBJECTIVES: In this study, by comparing the difference in protein expression in bronchoalveolar lavage fluid between silicosis patients in different stages and healthy controls, the pathogenesis of pneumoconiosis was discussed, and a new idea for the prevention and treatment of pneumoconiosis was provided. METHODS: The lung lavage fluid was pretreated by 10 K ultrafiltration tube, Agilent 1100 conventional liquid phase separation, strong cation exchange column (SCX) HPLC pre-separation, and C18 reverse phase chromatography desalting purification, and protein was labeled with isotope...

Opioid-related fatalities are a leading cause of accidental death in the United States. Appendicitis is a common cause of abdominal pain in children and adolescents. The management of pain throughout the laparoscopic appendectomy (LA) in the pediatric population is a critical concern. This study aimed to evaluate trends in analgesic use and patient satisfaction following LA, with a focus on reducing the reliance on opioids for pain management. From 2003 to 2023, 18258 articles were filtered for all types of analgesic use with LA...

BACKGROUND: Penicillin allergy is reported by 10-20 % of patients, but when evaluated only 1-2% may have a true allergy. Patients undergoing HSCT have a high likelihood of requiring beta-lactam antibiotics due to increased infection risk, which can be limited by a penicillin allergy label. When a penicillin allergy is recorded, alternatives are needed including more-expensive, broader-spectrum antibiotics, with increases in drug-resistant bacteria, longer hospital stays, higher expenditures, and increases in nosocomial infections such as C...