Structure-Based Design and Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High Selectivity, Brain Penetration, and In Vivo Efficacy.

Synthetic lethality has recently emerged as a new approach for the treatment of mutated genes that were previously considered undruggable. Targeting methionine adenosyltransferase 2A (MAT2A) in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality and thus has attracted significant interest in the field of precise anticancer drug development. Herein, we report the discovery of a series of novel MAT2A inhibitors featuring a pyrazolo[3,4-]quinolin-4-one skeleton based on structure-based drug design.

An Artificial Intelligence model for implant segmentation on periapical radiographs.

Objective: To segment dental implants on PA radiographs using a Deep Learning (DL) algorithm. To compare the performance of the algorithm relative to ground truth determined by the human annotator.

Methodology: Three hundred PA radiographs were retrieved from the radiographic database and consequently annotated to label implants as well as teeth on the LabelMe annotation software.

The Impact of Big Data Analytics on Decision-Making Within the Government Sector.

The government sector has started adopting big data analytics capability (BDAC) to enhance its service delivery. This study examines the relationship between BDAC and decision-making capability (DMC) in the government sector. It investigates the mediation role of the cognitive style of decision makers and organizational culture in the relationship between BDAC and DMC utilizing the resource-based view of the firm theory.

Myxoglobulosis of the appendix presenting as acute appendicitis.

Myxoglobulosis is a rare form of appendiceal mucocele characterized by mucoid material inside the appendix that resembles fish eggs. It is usually asymptomatic and diagnosed incidentally, but it can also present as a surgical abdomen, which can create a diagnostic dilemma. This case report presents a 37-year-old male patient with features suggestive of acute appendicitis.

An update on the discovery and development of reversible covalent inhibitors.

Small molecule drugs that covalently bind irreversibly to their target proteins have several advantages over conventional reversible inhibitors. They include increased duration of action, less-frequent drug dosing, reduced pharmacokinetic sensitivity, and the potential to target intractable shallow binding sites. Despite these advantages, the key challenges of irreversible covalent drugs are their potential for off-target toxicities and immunogenicity risks.

Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery.

The efficacy of oral insulin drug delivery is seriously hampered by multiple gastrointestinal barriers, especially transepithelial barriers, including apical endocytosis, lysosomal degradation, cytosolic diffusion and basolateral exocytosis. In this study, a functional nanoparticle (PG-FAPEP) with dual-modification was constructed to sequentially address these important absorption obstacles for improved oral insulin delivery. The dual surface decorations folate and charge-convertible tripeptide endowed PG-FAPEP with the ability to target the apical and basolateral sides of enterocytes, respectively.

Combining SVM and ECOC for Identification of Protein Complexes from Protein Protein Interaction Networks by Integrating Amino Acids' Physical Properties and Complex Topology.

Protein Complexes plays important role in key functional processes in cells by forming Protein Protein Interaction (PPI) networks. Conventionally, they were determined through experimental approaches. For the sake of saving time and cost reduction, many computational methods have been proposed.

Thermostability detection and optimization of glycoengineered antibodies and antibody-drug conjugates based on differential scanning flouremitry analysis.

Thermostability of monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), as a critical property of biotherapeutics, is important for their physicochemical processes, pharmacodynamics, and pharmacokinetics. Fc glycosylation of mAbs plays a crucial role in antibody functions including thermostability, however, due to the lack of homogeneous glycosylation for comparison, the precise impact of glycoforms on thermostability of mAbs and ADCs remains challenging to elucidate. In this paper, we employed the technique of differential scanning fluorimetry (DSF) to investigate the thermostability of Fc domains, glycoengineered mAbs, and ADCs, carrying well-defined N-glycan structures for comparison.

Evaluation of novel '-(3-hydroxybenzoyl)-2-oxo-2-chromene-3-carbohydrazide derivatives as potential HIV-1 integrase inhibitors.

In an attempt to identify potential new agents that are active against HIV-1 IN, a series of novel coumarin-3-carbohydrazide derivatives were designed and synthesised. The toxicity profiles of these compounds showed that they were non-toxic to human cells and they exhibited promising anti-HIV-1 IN activities with IC values in nM range. Also, an accompanying molecular modeling study showed that the compounds bind to the active pocket of the enzyme.

Design and Synthesis of Pyrophosphate-Targeting Vancomycin Derivatives for Combating Vancomycin-Resistant Enterococci.

As the last resort for intractable Gram-positive bacterial infections, vancomycin is losing efficacy with the emergence of vancomycin-resistant bacteria, especially vancomycin-resistant Enterococci (VRE). To combat this threat, we rationally designed and synthesized 39 novel vancomycin derivatives by respective or combined modifications using metal-chelating, lipophilic, and galactose-attachment strategies for extensive structure-activity relationship (SAR) analysis. In a proposed mechanism, the conjugation of dipicolylamine on the seventh amino acid resorcinol position or C-terminus endowed the vancomycin backbone with binding capacity for the pyrophosphate moiety in lipid II while maintaining the intrinsic binding affinity for the dipeptide terminus of the bacterial cell wall peptidoglycan precursor.

Synthesis and evaluation of substituted 4-arylimino-3-hydroxybutanoic acids as potential HIV-1 integrase inhibitors.

A series of readily accessible 4-arylimino-3-hydroxybutanoic acids have been prepared and evaluated as potential HIV-1 Integrase inhibitors. None of the ligands exhibited significant toxicity against human embryonic kidney (HEK 293) cells, while five of them showed activity against HIV-1 integrase - the most active (6c) with an IC value of 3.5 μM.

Synthesis and antimalarial activity of N-benzylated (N-arylcarbamoyl)alkylphosphonic acid derivatives.

A series of novel and readily accessible N-benzylated (N-arylcarbamoyl)alkylphosphonate esters and related compounds have been prepared as potential antimalarial agents. Bioassays reveal that some of these compounds exhibit promising activity against Plasmodium falciparum, and exhibit no significant growth inhibition of HeLa cells.

Synthesis and evaluation of substituted 4-(N-benzylamino)cinnamate esters as potential anti-cancer agents and HIV-1 integrase inhibitors.

Encouraging selectivity and low micromolar activity against HeLa cervical carcinoma (IC50⩾3.0μM) and the aggressive MDA-MB-231 triple negative breast carcinoma (IC50⩾9.6μM) cell lines has been exhibited by a number of readily accessible 4-(N-benzylamino)cinnamate esters.

An Update on the Status of Potent Inhibitors of Metallo-β-Lactamases.

The production of metallo-β-lactamases is the most important strategy by which pathogenic bacteria become resistant to currently known β-lactam antibiotics. The emergence of these enzymes is particularly concerning for the future treatment of bacterial infections. There are no clinically available drugs capable of inhibiting any of the metallo-β-lactamases, so there is an urgent need to find such inhibitors.

Penicillin inhibitors of purple acid phosphatase.

Purple acid phosphatases (PAPs) are binuclear metallohydrolases that have a multitude of biological functions and are found in fungi, bacteria, plants and animals. In mammals, PAP activity is linked with bone resorption and over-expression can lead to bone disorders such as osteoporosis. PAP is therefore an attractive target for the development of drugs to treat this disease.

3-mercapto-1,2,4-triazoles and N-acylated thiosemicarbazides as metallo-β-lactamase inhibitors.

The production of β-lactamases is an effective strategy by which pathogenic bacteria can develop resistance against β-lactam antibiotics. While inhibitors of serine-β-lactamases are widely used in combination therapy with β-lactam antibiotics, there are no clinically available inhibitors of metallo-β-lactamases (MBLs), and so there is a need for the development of such inhibitors. This work describes the optimisation of a lead inhibitor previously identified by fragment screening of a compound library.