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.

New constituents from Zanthoxylum rhoifolium Lam.

The phytochemical study of apolar and medium polarity stem bark and leaves extracts afforded twenty-nine compounds, including three new sesquiterpenes (1: -3: ) and one new α-ionone glycoside (4: ). All compounds were characterized by means of 1D and 2D NMR and HRESIMS data. Furthermore, a precise structural analysis was performed, employing a combined density functional theory (DFT)/NMR approach to elucidate the compounds configuration.

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).

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.

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.

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 Anticancer Potential of (Hochst.) Leaf Surface Extract: Discovering New Diterpenes as Heat Shock Protein 70 (Hsp70) Binding Agents.

, a genus consisting of approximately 200 species, predominantly thrives in tropical and subtropical areas. Many of these species have been utilized in ethnopharmacology for diverse medicinal applications. In Saudi Arabia, (Hochst.

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.

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.

Phytochemical Analysis of the Methanolic Extract and Essential Oil from Leaves of Industrial Hemp Cultivar: Isolation of a New Cannabinoid Derivative and Biological Profile Using Computational Approaches.

L. is a plant belonging to the Cannabaceae family, cultivated for its psychoactive cannabinoid (Δ-THC) concentration or for its fiber and nutrient content in industrial use. Industrial hemp shows a low Δ-THC level and is a valuable source of phytochemicals, mainly represented by cannabinoids, flavones, terpenes, and alkaloids, with health-promoting effects.

Diterpenoid Constituents of and Evaluation of Their Antimicrobial Activity.

Sixteen diterpenes (-), along with 10 previously described compounds, including four flavonoids and six diterpenes, were isolated from the aerial parts of growing in Saudi Arabia. The diterpene structures were elucidated using NMR spectroscopy and mass spectrometry data. Furthermore, a DFT/NMR procedure was used to suggest the relative configuration of several compounds.

Repositioning of Quinazolinedione-Based Compounds on Soluble Epoxide Hydrolase (sEH) through 3D Structure-Based Pharmacophore Model-Driven Investigation.

The development of new bioactive compounds represents one of the main purposes of the drug discovery process. Various tools can be employed to identify new drug candidates against pharmacologically relevant biological targets, and the search for new approaches and methodologies often represents a critical issue. In this context, in silico drug repositioning procedures are required even more in order to re-evaluate compounds that already showed poor biological results against a specific biological target.

Carnosol Attenuates LPS-Induced Inflammation of Cardiomyoblasts by Inhibiting NF-B: A Mechanistic and Study.

Carnosol possesses several beneficial pharmacological properties. However, its role in lipopolysaccharide (LPS) induced inflammation and cardiomyocyte cell line (H9C2) has never been investigated. Therefore, the effect of carnosol and an NF-B inhibitor BAY 11-7082 was examined, and the underlying role of the NF-B-dependent inflammatory pathway was analyzed as the target enzyme.

Cytotoxic Sesquiterpenoids from Aerial Parts.

Seven new terpenoids, namely, guaiane (-), eudesmane (), and bisabolane () sesquiterpenoids and a furanone (), were isolated from the aerial parts of , a herbaceous plant growing in Algeria, together with eight known compounds. All metabolites were characterized by their 1D and 2D NMR and HRESIMS data. A combined DFT/NMR method was applied to study the relative configurations of -, , and .

In Silico, In Vitro, and In Vivo Analysis of Tanshinone IIA and Cryptotanshinone from as Modulators of Cyclooxygenase-2/mPGES-1/Endothelial Prostaglandin EP3 Pathway.

Tanshinone IIA (TIIA) and cryptotanshinone (CRY) from Bunge were investigated for their inhibitory activity against the cyclooxygenase-2 (COX-2)/microsomal prostaglandin E synthase-1 (mPGES-1)/endothelial prostaglandin 3 (EP3) pathway using in silico, in vitro, in vivo, and ex vivo assays. From the analysis of the docking poses, both diterpenoids were able to interact significantly with COX-2, 5-lipoxygenase (5-LO), platelet-activating factor receptor (PAFR), and mPGES-1. This evidence was further corroborated by data obtained from a cell-free assay, where CRY displayed a significant inhibitory potency against mPGES-1 (IC = 1.

Insights into the Ligand Binding to Bromodomain-Containing Protein 9 (BRD9): A Guide to the Selection of Potential Binders by Computational Methods.

The estimation of the binding of a set of molecules against BRD9 protein was carried out through an in silico molecular dynamics-driven exhaustive analysis to guide the identification of potential novel ligands. Starting from eight crystal structures of this protein co-complexed with known binders and one form, we conducted an exhaustive molecular docking/molecular dynamics (MD) investigation. To balance accuracy and an affordable calculation time, the systems were simulated for 100 ns in explicit solvent.