drug discovery

Monkeypox virus (MPXV) core cysteine proteinase (CCP) is one of the major drug targets used to examine the inhibitory action of chemical moieties. In this study, an in silico technique was applied to screen 1395 anti-infective compounds to find out the potential molecules against the MPXV-CCP. The top five hits were selected after screening and processed for exhaustive docking based on the docked score of ≤ -9.5 kcal/mol. Later, the top three hits based on the exhaustive-docking score and interaction profile were selected to perform MD simulations...

Artificial intelligence and machine learning enable the construction of predictive models, which are currently used to assist in decision-making throughout the process of drug discovery and development. These computational models can be used to represent the heterogeneity of a disease, identify therapeutic targets, design and optimize drug candidates, and evaluate the efficacy of these drugs on virtual patients or digital twins. By combining detailed patient characteristics with the prediction of potential drug-candidate properties, artificial intelligence promotes the emergence of a "computational" precision medicine, allowing for more personalized treatments, better tailored to patient specificities with the aid of such predictive models...

Systemic sclerosis (SSc) with interstitial lung disease (SSc-ILD) lacks curative pharmacological treatments, thus necessitating effective animal models for candidate drug discovery. Existing Bleomycin (BLM)-induced SSc-ILD mouse models feature spatially limited pulmonary fibrosis, spontaneously resolving after 28 days. Here, we present an alternative BLM administration approach in female C57BL/6 mice, combining oropharyngeal aspiration (OA) and subcutaneous mini-pump delivery (pump) of BLM to induce a sustained and more persistent fibrosis, while retaining stable skin fibrosis...

UNLABELLED: The cellular surface of the pathogenic filamentous fungus Aspergillus fumigatus is enveloped in a mannose layer, featuring well-established fungal-type galactomannan and O -mannose-type galactomannan. This study reports the discovery of cell wall component in A. fumigatus mycelium, which resembles N -glycan outer chains found in yeast. The glycosyltransferases involved in its biosynthesis in A. fumigatus were identified, with a focus on two key α-(1→2)-mannosyltransferases, Mnn2 and Mnn5, and two α-(1→6)-mannosyltransferases, Mnn9 and Van1...

Vaska's complex is a prominent catalyst for the hydrosilylation of amides. The O -silyl hemiaminal intermediate formed in these processes has been demonstrated as an electrophile for nucleophilic additions. More recently, these intermediates have been shown to be suitable for single electron reduction to generate α-amino radicals. Leveraging the ability to generate α-amino radicals from these hemiaminals, we describe a two-step, one-pot, deoxy-arylation of amides utilizing iridium-catalyzed hydrosilylation and photoredox catalysis...

The management of oxidative stress-related disorders has garnered significant interest, particularly in the exploration of medicinal plants possessing potent antioxidant activities. This study was undertaken to evaluate the antioxidant activity of Mondia whitei (MW) and Guibourtia tessmannii (GT) against H2 O2 -induced cytotoxicity in PC3 cells. The phytochemical composition of MW and GT was determined by GC-MS analysis. Total phenolic (TP) and total flavonoid (TF) contents were quantified by Folin Ciocalteu and AlCl3 methods, respectively...

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...

Covering: 1993 to the end of 2022As the rapid development of antibiotic resistance shrinks the number of clinically available antibiotics, there is an urgent need for novel options to fill the existing antibiotic pipeline. In recent years, antimicrobial peptides have attracted increased interest due to their impressive broad-spectrum antimicrobial activity and low probability of antibiotic resistance. However, macromolecular antimicrobial peptides of plant and animal origin face obstacles in antibiotic development because of their extremely short elimination half-life and poor chemical stability...

The targeting of cancer cell intrinsic metabolism has emerged as a promising strategy for antitumor intervention. In the study, we identified the first-in-class small molecules that effectively inhibit both mutant isocitrate dehydrogenase 1 (mIDH1) and nicotinamide phosphoribosyltransferase (NAMPT), two crucial targets in cancer metabolism, through structure-based drug design. Notably, compound 23h exhibits excellent and balanced inhibitory activities against both mIDH1 (IC50 = 14.93 nM) and NAMPT (IC50 = 12...

Artificial intelligence (AI) de novo molecular generation is a highly promising strategy in the drug discovery, with deep reinforcement learning (RL) models emerging as powerful tools. This study introduces a fragment-by-fragment growth RL forward molecular generation and optimization strategy based on a low activity lead compound. This process integrates fragment growth-based reaction templates, while target docking and drug-likeness prediction were simultaneously performed. This comprehensive approach considers molecular similarity, internal diversity, synthesizability, and effectiveness, thereby enhancing the quality and efficiency of molecular generation...

Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe hemorrhagic fever in humans. With high mortality rates and limited treatment options, the search for effective antivirals is imperative. Current treatments, notably ribavirin and other nucleoside inhibitors, are only partially effective and have significant side effects. The high lethality and lack of treatment, coupled with the absence of vaccines for all but Junín virus, has led to the classification of these viruses as Category A pathogens by the Centers for Disease Control (CDC)...

BACKGROUND: Stroke is a disease with high morbidity, disability, and mortality. Immune factors play a crucial role in the occurrence of ischemic stroke (IS), but their exact mechanism is not clear. This study aims to identify possible immunological mechanisms by recognizing immune-related biomarkers and evaluating the infiltration pattern of immune cells. METHODS: We downloaded datasets of IS patients from GEO, applied R language to discover differentially expressed genes, and elucidated their biological functions using GO, KEGG analysis, and GSEA analysis...

INTRODUCTION: Immune defense mechanisms, including a decrease in the functional activity of monocytes/macrophages, neutrophils, as well as a violation of the balance of pro- and anti-inflammatory cytokines, are important in the development of chronic abacterial prostatitis (CAP). The discovery of the cytokine system and the determination of their biological role in the development and functioning of the immune system and in the pathogenesis of a wide range of human diseases led to the development of a new direction in immunotherapy - cytokine therapy...

A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) and human lung adenocarcinoma cells (NCI-H1437) as non-small cell lung cancer. In comparison to gefitinib, Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines...

The long treatment period and development of drug resistance in tuberculosis (TB) necessitates the discovery of new anti-tubercular agents. The drug discovery program of the institute leads to the development of an anti-tubercular lead (IIIM-019), which is an analogue of nitrodihydroimidazooxazole and exhibited promising anti-tubercular action. However, IIIM-019 displays poor aqueous solubility (1.2 µg/mL), which demands suitable dosage form for its efficient oral administration. In the present study, third generation solid dispersion-based formulation was developed to increase the solubility and dissolution of IIIM-019...

Hepatitis B and C viruses (HBV and HCV) are significant causes of chronic liver diseases, with approximately 350 million infections globally. To accelerate the finding of effective treatment options, we introduce HBCVTr, a novel ligand-based drug design (LBDD) method for predicting the inhibitory activity of small molecules against HBV and HCV. HBCVTr employs a hybrid model consisting of double encoders of transformers and a deep neural network to learn the relationship between small molecules' simplified molecular-input line-entry system (SMILES) and their antiviral activity against HBV or HCV...

The Tetraspanins (Tspan) protein family, also known as the tetraspanin family, contains 33 family members that interact with other protein molecules such as integrins, adhesion molecules, and T cell receptors by forming dimers or heterodimers. The Tspan protein family regulates cell proliferation, cell cycle, invasion, migration, apoptosis, autophagy, tissue differentiation, and immune response. More and more studies have shown that Tspan proteins are involved in tumorigenesis, epithelial-mesenchymal transition, thrombosis, tumor stem cell, and exosome signaling...

Voltage-gated ion channels are transmembrane proteins responsible for the generation and propagation of action potentials in excitable cells. In the past few years, crystal structures of ion channels have become accessible and, when combined with mutagenesis data, have aided in the discovery of drugs that can modulate ion conduction. However, many traditional drugs lack selectivity and come with adverse side effects. The emergence of photopharmacology has provided an orthogonal way of controlling the activity of compounds, enabling the regulation of ion conduction with light...

Chinchillas are a relatively novel research model compared with other rodent species. They require special considerations when it comes to their husbandry and daily care. Chinchillas tend to be shy animals that are well adapted to masking clinical signs of illness. These characteristics can make them a difficult species to maintain in a research setting. The authors' institution has maintained chinchillas and established standardized daily animal care procedures for them. Chinchillas are most commonly used for auditory research...

The escalating crisis of antimicrobial resistance (AMR) underscores the urgent need for novel antimicrobials. One promising strategy is the exploration of structural diversity, as diverse structures can lead to diverse biological activities and mechanisms of action. This review delves into the role of structural diversity in antimicrobial discovery, highlighting its influence on factors such as target selectivity, binding affinity, pharmacokinetic properties, and the ability to overcome resistance mechanisms...