5-methyl-2-carboxamidepyrrole-based novel dual mPGES-1/sEH inhibitors as promising anticancer candidates.

Inhibiting microsomal prostaglandin E synthase-1 (mPGES-1), an inducible enzyme involved in prostaglandin E (PGE) biosynthesis and tumor microenvironment (TME) homeostasis, is a valuable strategy for treating inflammation and cancer. In this work, 5-methylcarboxamidepyrrole-based molecules were designed and synthesized as new compounds targeting mPGES-1. Remarkably, compounds 1f, 2b, 2c, and 2d were able to significantly reduce the activity of the isolated enzyme, showing IC values in the low micromolar range.

Identification of a New Promising BAG3 Modulator Featuring the Imidazopyridine Scaffold.

The antiapoptotic BAG3 protein plays a crucial role in cellular proteostasis and it is involved in several signalling pathways governing cell proliferation and survival. Owing to its multimodular structure, it possesses an extensive interactome including the molecular chaperone HSP70 and other specific cellular partners, which make it an eminent factor in several pathologies, particularly in cancer. Despite its potential as a therapeutic target, very few BAG3 modulators have been disclosed so far.

Chemical Profiling of Polar Lipids and the Polyphenolic Fraction of Commercial Italian Seeds by UHPLC-HRMS and Biological Evaluation.

The common bean ( L.) is one of the oldest food crops in the world. In this study, the ultra-high-performance liquid chromatography high-resolution mass spectrometry (UHPLC-MS/MS) technique was used to characterize the polar lipid composition and polyphenolic fraction of five bean varieties commonly consumed in Italy: Cannellino (PVCA), Controne (PVCO), Borlotti (PVBO), Stregoni (PVST), and Vellutina (PVVE).

Combined awake videolaryngo-bronchoscopy intubation with HFNC preoxygenation for predicted difficult airway in a patient with post-burn mentosternal scar contracture.

Airway management and safety remain a difficult challenge during reconstructive surgery in patients with extensive post-burn mentosternal scar contractures. Current guidelines do not recommend the use of direct laryngoscopy for predicted difficult airway because of the risk of intubation failure and airway emergencies: the consequences of wrong decisions can be fatal, and the patient is at serious risk. At present, video-laryngoscopy is the most commonly used technique for routine orotracheal intubation.

Identification of Novel Bromodomain-Containing Protein 4 (BRD4) Binders through 3D Pharmacophore-Based Repositioning Screening Campaign.

A 3D structure-based pharmacophore model built for bromodomain-containing protein 4 (BRD4) is reported here, specifically developed for investigating and identifying the key structural features of the (+)-JQ1 known inhibitor within the BRD4 binding site. Using this pharmacophore model, 273 synthesized and purchased compounds previously considered for other targets but yielding poor results were screened in a drug repositioning campaign. Subsequently, only six compounds showed potential as BRD4 binders and were subjected to further biophysical and biochemical assays.

In Silico Design, Chemical Synthesis, Biophysical and in Vitro Evaluation for the Identification of 1-Ethyl-1H-Pyrazolo[3,4-b]Pyridine-Based BRD9 Binders.

In this work, we report the identification of novel bromodomain-containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure-based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1-ethyl-1H-pyrazolo[3,4-b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C-4 and C-6 positions of the central core.

Essential Oils of L.: From Chemical Analysis to In Silico Investigation of Anti-Inflammatory Activity by Soluble Epoxide Hydrolase (sEH) Inhibition.

L. is commonly used in folk medicine in the form of infusion or decoction to treat gastrointestinal diseases and flatulence as a carminative, antiseptic, and anti-inflammatory agent. In this study, the essential oil (EO) composition of wild-grown L.

Fatty Acid Synthase as Interacting Anticancer Target of the Terpenoid Myrianthic Acid Disclosed by MS-Based Proteomics Approaches.

This research focuses on the target deconvolution of the natural compound myrianthic acid, a triterpenoid characterized by an ursane skeleton isolated from the roots of and from Nutt. (Onagraceae), using MS-based chemical proteomic techniques. Application of drug affinity responsive target stability (DARTS) and targeted-limited proteolysis coupled to mass spectrometry (t-LiP-MS) led to the identification of the enzyme fatty acid synthase (FAS) as an interesting macromolecular counterpart of myrianthic acid.

Repositioning of Small Molecules through the Inverse Virtual Screening in silico Tool: Case of Benzothiazole-Based Inhibitors of Soluble Epoxide Hydrolase (sEH).

Computational techniques accelerate drug discovery by identifying bioactive compounds for specific targets, optimizing molecules with moderate activity, or facilitating the repositioning of inactive items onto new targets. Among them, the Inverse Virtual Screening (IVS) approach is aimed at the evaluation of one or a small set of molecules against a panel of targets for addressing target identification. In this work, a focused library of benzothiazole-based compounds was re-investigated by IVS.

PharmaCore: The Automatic Generation of 3D Structure-Based Pharmacophore Models from Protein/Ligand Complexes.

In this work, we present PharmaCore: a new, completely automatic workflow aimed at generating three-dimensional (3D) structure-based pharmacophore models toward any target of interest. The proposed approach relies on using cocrystallized ligands to create the input files for generating the pharmacophore hypotheses, integrating not only the three-dimensional structural information on the ligand but also data concerning the binding mode of these molecules put in the protein cavity. We developed a Python library that, starting from the specific UniProt ID of the protein under investigation as the only element that requires user intervention, subsequently collects and aligns the corresponding structures bearing a known ligand in a fully automated fashion, bringing them all into the same coordinate system.

Identification and Development of BRD9 Chemical Probes.

The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure-activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research.

Long-term functional outcomes and surgical retreatment after thulium laser enucleation of the prostate: A 10-year follow-up study.

Background: To evaluate the 10-year functional outcomes (primary) and frequency and predictors of BPH surgical retreatment (secondary) after ThuLEP.

Materials And Methods: A single-center retrospective analysis of consecutive patients undergoing ThuLEP between 2010 and 2013 was performed. Inclusion criteria were: age ≥ 40 years, prostate volume (PV) ≥ 80 mL, International Prostate Symptom Score (IPSS)-Total score ≥ 8 points.

NMR Metabolomics and Chemometrics of Commercial Varieties of L. Seeds from Italy and In Vitro Antioxidant and Antifungal Activity.

The metabolite fingerprinting of four Italian commercial bean seed cultivars, i.e., Cannellino (PCANN), Controne (PCON), Vellutina (PVEL), and Occhio Nero (PON), were investigated by Nuclear Magnetic Resonance (NMR) spectroscopy and multivariate data analysis.

Chemoproteomics Reveals USP5 (Ubiquitin Carboxyl-Terminal Hydrolase 5) as Promising Target of the Marine Polyketide Gracilioether A.

Mass spectrometry-based chemical proteomic approaches using limited proteolysis have become a powerful tool for the identification and analysis of the interactions between a small molecule (SM) and its protein target(s). Gracilioether A (GeA) is a polyketide isolated from a marine sponge, for which we aimed to trace the interactome using this strategy. DARTS (Drug Affinity Responsive Target Stability) and t-LiP-MS (targeted-Limited Proteolysis-Mass Spectrometry) represented the main techniques used in this study.

Peptidomimetics as potent dual SARS-CoV-2 cathepsin-L and main protease inhibitors: In silico design, synthesis and pharmacological characterization.

In this paper we present the design, synthesis, and biological evaluation of a new series of peptidomimetics acting as potent anti-SARS-CoV-2 agents. Starting from our previously described Main Protease (M) and Papain Like Protease (PL) dual inhibitor, CV11, here we disclose its high inhibitory activity against cathepsin L (CTSL) (IC = 19.80 ± 4.

Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species.

Alzheimer's disease is the most common age-associated neurodegenerative disorder and the most frequent form of dementia in our society. Aging is a complex biological process concurrently shaped by genetic, dietary and environmental factors and natural compounds are emerging for their beneficial effects against age-related disorders. Besides their antioxidant activity often described in simple model organisms, the molecular mechanisms underlying the beneficial effects of different dietary compounds remain however largely unknown.

2-Substituted 1,5-benzothiazepine-based HDAC inhibitors exert anticancer activities on human solid and acute myeloid leukemia cell lines.

Herein, we report the development of a new series of histone deacetylase inhibitors (HDACi) containing a 2-substituted 1,5-benzothiazepine scaffold. First, a virtual combinatorial library (∼1.6 × 10 items) was built according to a convenient synthetic route, and then it was submitted to molecular docking experiments on seven HDACs isoforms belonging to classes I and II.

Exploring the chemical space of functionalized [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the bromodomain of BRD9.

Here we report a detailed structure-activity relationship (SAR) study related to [1,2,4]triazolo[4,3-a]quinoxaline-based compounds targeting the reader module of bromodomain containing-protein 9 (BRD9). 3D structure-based pharmacophore models, previously introduced by us, were here employed to evaluate a second generation of compounds, exploring different substitution patterns on the heterocyclic core. Starting from the promising data obtained from our previously identified [1,2,4]triazolo[4,3-a]quinoxaline-based compounds 1-4, the combination of in silico studies, chemical synthesis, biophysical and in vitro assays led to the identification of a new set of derivatives, selected for thoroughly exploring the chemical space of the bromodomain binding site.

Measuring social norms and attitudes about age-disparate transactional sex: Psychometric testing of the NAATSS.

Background: Transactional sex between girls under 18 years-old and adult men at least ten years older, known as age-disparate transactional sex (ADTS), is an established risk factor for HIV, STI and early pregnancy among girls and women. Social norms or beliefs about what others expect from you and what others do can sustain behaviours such as ADTS even when individuals may be personally against them. In order to evaluate interventions to change social norms, validated instruments for measuring change in personal beliefs and social norms regarding ADTS are needed.

Target identification by structure-based computational approaches: Recent advances and perspectives.

The use of computational techniques in the early stages of drug discovery has recently experienced a boost, especially in the target identification step. Finding the biological partner(s) for new or existing synthetic and/or natural compounds by "wet" approaches may be challenging; therefore, preliminary in silico screening is even more recommended. After a brief overview of some of the most known target identification techniques, recent advances in structure-based computational approaches for target identification are reported in this digest, focusing on Inverse Virtual Screening and its recent applications.

Identification of 2-Aminoacyl-1,3,4-thiadiazoles as Prostaglandin E and Leukotriene Biosynthesis Inhibitors.

The application of a multi-step scientific workflow revealed an unprecedented class of PGE/leukotriene biosynthesis inhibitors with activity. Specifically, starting from a combinatorial virtual library of ∼4.2 × 10 molecules, a small set of compounds was identified for the synthesis.

Identification of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based small molecules as selective BRD9 binders.

Targeting bromodomain-containing protein 9 (BRD9) represents a promising strategy for the development of new agents endowed with anticancer properties. With this aim, a set of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based compounds was investigated following a combined approach that relied on in silico studies, chemical synthesis, biophysical and biological evaluation of the most promising items. The protocol was initially based on molecular docking experiments, accounting a library of 1896 potentially synthesizable items tested in silico against the bromodomain of BRD9.