WaSPred: A reliable AI-based water solubility predictor for small molecules.

A rapid and reliable evaluation of the aqueous solubility of small molecules is a hot topic for the scientific community and represents a field of particular interest in drug discovery. In fact, aqueous solubility significantly impacts various aspects that collectively influence a drug's overall pharmacokinetics, including absorption, distribution and metabolism. For this reason, in silico approaches that provide fast and cost-effective solubility predictions, can serve as invaluable tools in the early stages of drug development.

A patent review of lactate dehydrogenase inhibitors (2014-present).

Introduction: Lactate dehydrogenase (LDH) is a key enzyme in glycolysis responsible for the conversion of pyruvate into lactate and vice versa. Lactate plays a crucial role in tumor progression and metastasis; therefore, reducing lactate production by inhibiting LDH is considered an optimal strategy to tackle cancer. Additionally, dysregulation of LDH activity is correlated with other pathologies, such as cardiovascular and neurodegenerative diseases as well as primary hyperoxaluria, fibrosis and cryptosporidiosis.

Glycoconjugate coumarins exploiting metabolism-enhanced fluorescence and preferential uptake: New optical tools for tumor cell staining.

The possibility to visually discriminate cells based on their metabolism and capability to uptake exogenous molecules is an important topic with exciting fallback on translational and precision medicine. To this end, probes that combine several complementary features are necessary. The ideal probe is selectively uptaken and activated in tumor cells compared with control ones and is not fluorescent in the extracellular medium.

Effects of lactate dehydrogenase A and GLUT1 inhibition on human endothelial cell migration in relation to their intracellular nucleotide pool.

The expression of both lactate dehydrogenase A (LDH-A) and glucose transporter type 1 (GLUT1) is high in pancreatic, thoracic and many other types of cancer. GLUT1 is also highly expressed in endothelial cells (EC), that play an important role in tumor metastasis. We investigated the effect of inhibition of LDH-A by NHI-2 and GLUT1 by PGL14 on cellular migration, a hallmark of metastasis, in relation to changes in intracellular purine nucleotide and nicotinamide adenine dinucleotide pools in a human microvascular endothelial cell line (HMEC-1).

A carrier free delivery system of a MAGL inhibitor is effective on ovarian cancer.

Monoacylglycerol lipase (MAGL) is a promising target for cancer therapy due to its involvement in lipid metabolism and its impact on cancer hallmarks like cell proliferation, migration, and tumor progression. A potent reversible MAGL inhibitor, MAGL23, has been recently developed by our group, demonstrating promising anticancer activities. To enhance its pharmacological properties, a nanoformulation using nanocrystals coated with albumin was prepared (MAGL23AF).

Evaluation of the combination of gemcitabine, carboplatin, and lactate dehydrogenase A inhibitor on malignant mesothelioma.

Objectives: Lactate dehydrogenase A (LDH-A) catalyzes the last step of glycolysis: supplying cells rapidly but inefficiently with ATP. Many tumors, including malignant mesothelioma (MM), have a high expression of LDH-A, which is associated with cancer aggressiveness. We aimed to determine whether the efficacy of the gemcitabine/carboplatin (Gem + Carbo) combination, widely used to treat this disease, could be increased by inhibition of LDH-A (by NHI-2).

Watermelon: setup and validation of an fragment-based approach.

We present a new computational approach, named , designed for the development of pharmacophore models based on receptor structures. The methodology involves the sampling of potential hotspots for ligand interactions within a protein target's binding site, utilising molecular fragments as probes. By employing docking and molecular dynamics (MD) simulations, the most significant interactions formed by these probes within distinct regions of the binding site are identified.

The Benzoylpiperidine Fragment as a Privileged Structure in Medicinal Chemistry: A Comprehensive Review.

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties. The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000.

SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common among children. AML is characterized by aberrant proliferation of myeloid blasts in the bone marrow and impaired normal hematopoiesis. Despite the introduction of new drugs and allogeneic bone marrow transplantation, patients have poor overall survival rate with relapse as the major challenge, driving the demand for new therapeutic strategies.

Sirtuin 1-activating derivatives belonging to the anilinopyridine class displaying cardioprotective activities.

Sirtuin 1 (SIRT1) is an enzyme that relies on NAD cofactor and functions as a deacetylase. It has been associated with various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. Recent studies have shown that compounds that activate SIRT1 exhibit protective effects on the heart.

Identification of New GSK3β Inhibitors through a Consensus Machine Learning-Based Virtual Screening.

Glycogen synthase kinase-3 beta (GSK3β) is a serine/threonine kinase that plays key roles in glycogen metabolism, Wnt/β-catenin signaling cascade, synaptic modulation, and multiple autophagy-related signaling pathways. GSK3β is an attractive target for drug discovery since its aberrant activity is involved in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In the present study, multiple machine learning models aimed at identifying novel GSK3β inhibitors were developed and evaluated for their predictive reliability.

Design, synthesis, ADME and biological evaluation of benzylpiperidine and benzylpiperazine derivatives as novel reversible monoacylglycerol lipase (MAGL) inhibitors.

The degradation of the endocannabinoid 2-arachidonoylglycerol is mediated by the enzyme monoacylglycerol lipase (MAGL), thus generating arachidonic acid, the precursor of prostaglandins and other pro-inflammatory mediators. MAGL also contributes to the hydrolysis of monoacylglycerols into glycerol and fatty acids in peripheral body districts, which may act as pro-tumorigenic signals. For this reason, MAGL inhibitors have been considered as interesting therapeutic agents for their anti-nociceptive, anti-inflammatory, antioxidant and anti-cancer properties.

Combined inhibition of pyruvate dehydrogenase kinase 1 and lactate dehydrogenase a induces metabolic and signaling reprogramming and enhances lung adenocarcinoma cell killing.

Lung adenocarcinoma (LUAD) is one of the most prevalent and aggressive types of lung cancer. Metabolic reprogramming plays a critical role in the development and progression of LUAD. Pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are two key enzymes involved in glucose metabolism, whilst their aberrant expressions are often associated with tumorigenesis.

VenomPred 2.0: A Novel Platform for an Extended and Human Interpretable Toxicological Profiling of Small Molecules.

The application of artificial intelligence and machine learning (ML) methods is becoming increasingly popular in computational toxicology and drug design; it is considered as a promising solution for assessing the safety profile of compounds, particularly in lead optimization and ADMET studies, and to meet the principles of the 3Rs, which calls for the replacement, reduction, and refinement of animal testing. In this context, we herein present the development of VenomPred 2.0 (http://www.

First-in-Class Dual Targeting Compounds for the Management of Seizures in Glucose Transporter Type 1 Deficiency Syndrome.

The genetic disorder glucose transporter type 1 deficiency syndrome (GLUT1-DS) heavily affects the main intake of energy in tissues and determines the most relevant outcomes at the central nervous system (CNS) district, which is highly dependent on glucose. Herein, we report the design and development of a set of compounds bearing the glucosyl and galactosyl moieties. We assessed their ability to enhance the GLUT1 mediated glucose intake in non-small-cell lung cancer (NSCLC) cells and to inhibit the carbonic anhydrase (CA; EC 4.

Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma.

Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. The prognostic role of key effectors of glycolytic metabolism in MM prompted our studies on the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD metabolism, glycolysis and mitochondrial respiration. The antiproliferative activity of GLUT-1 (PGL13, PGL14) and LDH-A (NHI-1, NHI-2) inhibitors, alone and in combination, were tested with the sulforhodamine-B assay in peritoneal (MESO-II, STO) and pleural (NCI-H2052 and NCI-H28) MM and non-cancerous (HMEC-1) cells.

Functionalized aliphatic polyketones with germicide activity.

The COVID-19 pandemic has further confirmed to the community that direct contact with contaminated surfaces and objects represents an important source of pathogen spreading among humans. Therefore, it is of paramount importance to design effective germicidal paints to ensure a rapid and potent disinfectant action of surfaces. In this work, we design novel germicide polymeric coatings by inserting quaternary ammonium and sugar groups on the macromolecular backbone, thus respectively endowing the polymer with germicide features and hydrophilicity to interact with the surfaces.

Sirtuin 1-Activating Compounds: Discovery of a Class of Thiazole-Based Derivatives.

Sirtuin 1 (SIRT1) is a NAD-dependent deacetylase implicated in various biological and pathological processes, including cancer, diabetes, and cardiovascular diseases. In recent years, SIRT1-activating compounds have been demonstrated to exert cardioprotective effects. Therefore, this enzyme has become a feasible target to treat cardiovascular diseases, and many SIRT1 activators, of a natural or synthetic origin, have been identified.

Machine Learning-Based Virtual Screening for the Identification of Cdk5 Inhibitors.

Cyclin-dependent kinase 5 (Cdk5) is an atypical proline-directed serine/threonine protein kinase well-characterized for its role in the central nervous system rather than in the cell cycle. Indeed, its dysregulation has been strongly implicated in the progression of synaptic dysfunction and neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and also in the development and progression of a variety of cancers. For this reason, Cdk5 is considered as a promising target for drug design, and the discovery of novel small-molecule Cdk5 inhibitors is of great interest in the medicinal chemistry field.

MAGL inhibitor NanoMicellar formulation (MAGL-NanoMicellar) for the development of an antiglaucoma eye drop.

The ocular endocannabinoid system (ECS) including enzymes and CB1/CB2 receptors determines various substantial effects, such as anti-inflammatory activity and reduction of the intraocular pressure (IOP). The modulation of 2-arachidonoylglycerol (2-AG) levels obtained via MAGL inhibition is considered as a promising pharmacological strategy to activate the ECS. Within the scope of this study, the effect of a selective monoacylglycerol lipase (MAGL) inhibitor (MAGL17b) was investigated by measuring the IOP reduction in normotensive rabbits after performing a solubilisation process of the molecule with non-ionic surfactants, to produce suitable eye drops containing the highest possible concentration of the drug.

Historical perspective of tumor glycolysis: A century with Otto Warburg.

Tumors have long been known to rewire their metabolism to endorse their proliferation, growth, survival, and invasiveness. One of the common characteristics of these alterations is the enhanced glucose uptake and its subsequent transformation into lactic acid by means of glycolysis, regardless the availability of oxygen or the mitochondria effectiveness. This phenomenon is called the "Warburg effect", which has turned into a century of age now, since its first disclosure by German physiologist Otto Heinrich Warburg.

Biological Activity of Natural and Synthetic Compounds.

A drug discovery program starts when a disease or clinical condition has no suitable drugs [...

Reversible Monoacylglycerol Lipase Inhibitors: Discovery of a New Class of Benzylpiperidine Derivatives.

Monoacylglycerol lipase (MAGL) is the enzyme responsible for the metabolism of 2-arachidonoylglycerol in the brain and the hydrolysis of peripheral monoacylglycerols. Many studies demonstrated beneficial effects deriving from MAGL inhibition for neurodegenerative diseases, inflammatory pathologies, and cancer. MAGL expression is increased in invasive tumors, furnishing free fatty acids as pro-tumorigenic signals and for tumor cell growth.

ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective.

Introduction: ATP citrate lyase (ACLY) is a key enzyme in cellular metabolism, being the main source of acetyl-Coenzyme A, an important precursor for fatty acid, cholesterol, and isoprenoid biosynthesis, and it is also involved in protein acetylation. Its expression changes are related to hyperlipidemia and cardiovascular diseases. Other studies have shown that ACLY is closely related to the occurrence of cancer: the increase in lipid synthesis provides the necessary building blocks for cell growth and division.

New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds.

NAD-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures.