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Molecular docking studies confirmed the binding of lesbicoumestan to the active site of MALT1. [...]lesbicoumestan showed apoptotic effects on human leukemia cells by several mechanisms: it increased mitochondrial reactive oxygen species, activated caspase-dependent pathways and decreased the mRNA expression level of antioxidant genes. Blažíčková et al. focused their research on a natural compound extracted from the herb Thymus vulgaris, thymol, whose use was greatly limited by its hydrophobic properties. [...]more hydrophilic derivatives were synthesized or purchased with the aim of improving cell permeability with respect to the parent compound. Considering the widely reported biological activities of pyrrolo[1,2-a]quinoline derivatives, a novel series of synthetic compounds possessing this scaffold were screened in vitro on Candida albicans, and molecular modeling studies were performed against C. albicans pathogenic proteins. [...]the exploration of the possible off-targets and ADME parameters were determined by in silico studies, revealing good drug-like properties for the newly identified antifungal molecules [12]. [13], probably due to the features of imidazole heterocycle that are a high polarity and the ability to participate in hydrogen bonds, thus facilitating the interaction with biological targets. [...]kinase inhibitors reported in the literature are often characterized by different heterocyclic cores, and, interestingly, most of them found applications in the treatment of neuroblastoma, both at the preclinical and clinical levels [14].

Computer-aided drug design techniques are today largely applied in medicinal chemistry. In particular, receptor-based virtual screening (VS) studies, in which molecular docking represents the gold standard in silico approach, constitute a powerful strategy for identifying novel hit compounds active against the desired target receptor. Nevertheless, the need for improving the ability of docking in discriminating true active ligands from inactive compounds, thus boosting VS hit rates, is still pressing. In this context, the use of binding free energy evaluation approaches can represent a profitable tool for rescoring ligand-protein complexes predicted by docking based on more reliable estimations of ligand-protein binding affinities than those obtained with simple scoring functions. In the present review, we focused our attention on the Molecular Mechanics-Poisson Boltzman Surface Area (MM-PBSA) method for the calculation of binding free energies and its application in VS studies. We provided examples of successful applications of this method in VS campaigns and evaluation studies in which the reliability of this approach has been assessed, thus providing useful guidelines for employing this approach in VS.

Current tumor diagnostics rely on fluorodeoxyglucose (FDG)-PET imaging, but FDG’s short half-life and high cost limit its widespread use. Infrared (IR) probes are emerging as non-radioactive alternatives to conventional tracers for tissue section and other in vitro imaging applications. Because cells and tissues are relatively free of absorption peaks between 1800 and 2200 cm−1, metal-carbonyl complexes, especially cyclopentadienylrhenium(I) tricarbonyl (Cp[Re(CO)3]) derivatives, absorb strongly in this window and provide robust platforms for bioconjugation. Furthermore, Cp[Re(CO)3] fragments can be introduced into organic substrates via an elegant three-component reaction that simultaneously forges the cyclopentadienyl-metal and cyclopentadienyl-substituent bonds. As a result, the functionalized half-sandwich complex is obtained in a single step without any special handling issues. We have therefore properly modified a glucose molecule with that complex and developed a novel glucoconjugated Cp[Re(CO)3] probe that enables IR-based visualization of diseased cells at 2100 cm−1, offering a non-invasive, non-radioactive histological tool and a promising basis for future medical imaging devices.

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. A specific section is focused on the synthetic strategies adopted to obtain this versatile chemical portion.

Monoacylglycerol lipase (MAGL) is a key serine hydrolase involved in lipid metabolism, catalyzing the hydrolysis of monoacylglycerols into free fatty acids and glycerol. MAGL plays a central role in regulating endocannabinoid signaling and lipid homeostasis, processes often dysregulated in cancer and other pathological conditions. In recent years, MAGL has emerged as a promising therapeutic target, particularly in oncology, where its inhibition has shown potential to impair tumor growth, metastasis, and inflammation-driven processes. Alongside the development of selective MAGL inhibitors, several biochemical methods have been established to measure MAGL enzymatic activity, providing essential tools for target validation and inhibitor characterization. In this review, we provide a comprehensive and critical overview of the main approaches developed for MAGL activity evaluation, including radiometric, chromatographic, colorimetric, fluorescence-based, bioluminescence-based, and activity-based protein profiling (ABPP) assays. For each method, we discuss principles, advantages, and limitations. This review aims to support researchers in the selection of the most appropriate assay strategy for their experimental needs, ultimately fostering the rapid and accurate development of novel MAGL inhibitors with potential applications in cancer therapy and metabolic disease management.

Some musculoskeletal disorders, including osteoarthritis; arthrosis; post-traumatic injuries; and other inflammatory tendon, joint and muscular afflictions, still represent unmet medical needs. Cetylated fatty acids (CFAs) are key components of widely distributed over-the-counter products, especially for topical use, which are intended to reduce symptoms associated with these conditions. Nevertheless, the mechanism of action of CFAs’ analgesic and anti-inflammatory properties has not yet been clearly established. Endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), are known to produce analgesic and anti-inflammatory effects. These compounds undergo physiological inactivation operated by several enzymes, including monoacylglycerol lipase (MAGL). We herein demonstrate for the first time that the therapeutic effects of CFAs may be attributable, at least in part, to their MAGL inhibition activities, which induce a local increase in analgesic/anti-inflammatory endocannabinoids in close proximity to the site of administration. These findings pave the way for the development of new potent local analgesic agents, whose action is based on an indirect cannabinoid effect.

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. AML patients with high expression of the very long/long chain fatty acid transporter CD36 have poorer survival and very long chain fatty acid metabolism is critical for AML cell survival. Here we show that fatty acids are transferred from human primary adipocytes to AML cells upon co-culturing. A drug-like small molecule (SMS121) was identified by receptor-based virtual screening and experimentally demonstrated to target the lipid uptake protein CD36. SMS121 reduced the uptake of fatty acid into AML cells that could be reversed by addition of free fatty acids and caused decreased cell viability. The data presented here serves as a framework for the development of CD36 inhibitors to be used as future therapeutics against AML.

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. These interactions are subsequently transformed into pharmacophore features that delineates key anchoring sites for potential ligands. The reliability of the approach was experimentally validated using the monoacylglycerol lipase (MAGL) enzyme. The generated pharmacophore model captured features representing ligand-MAGL interactions observed in various X-ray co-crystal structures and was employed to screen a database of commercially available compounds, in combination with consensus docking and MD simulations. The screening successfully identified two new MAGL inhibitors with micromolar potency, thus confirming the reliability of the approach.

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. In the present work, we developed thiazole-based SIRT1 activators, which showed remarkably higher SIRT1 activation potencies compared with those of the reference compound resveratrol when tested in enzymatic assays. Thiazole 8, a representative compound of this series, was also subjected to further pharmacological investigations, where it was proven to reduce myocardial damage induced by an in vivo occlusion/reperfusion event, thus confirming its cardioprotective properties. In addition, the cardioprotective effect of compound 8 was significantly higher than that of resveratrol. Molecular modeling studies suggest the binding mode of these derivatives within SIRT1 in the presence of the p53-AMC peptide. These promising results could pave the way to further expand and optimize this chemical class of new and potent SIRT1 activators as potential cardioprotective agents.

Therapies that target the signal transduction and metabolic pathways of cancer stem cells (CSCs) are innovative strategies to effectively reduce the recurrence and significantly improve the outcome of glioblastoma multiforme (GBM). CSCs exhibit an increased rate of glycolysis, thus rendering them intrinsically more sensitive to prospective therapeutic strategies based on the inhibition of the glycolytic pathway. The enzyme lactate dehydrogenase-A (LDH-A), which catalyses the interconversion of pyruvate and lactate, is up-regulated in human cancers, including GBM. Although several papers have explored the benefits of targeting cancer metabolism in GBM, the effects of direct LDH-A inhibition in glial tumours have not yet been investigated, particularly in the stem cell subpopulation. Here, two representative LDH-A inhibitors ( NHI-1 and NHI-2 ) were studied in GBM-derived CSCs and compared to differentiated tumour cells. LDH-A inhibition was particularly effective in CSCs isolated from different GBM cell lines, where the two compounds blocked CSC formation and elicited long-lasting effects by triggering both apoptosis and cellular differentiation. These data demonstrate that GBM, particularly the stem cell subpopulation, is sensitive to glycolytic inhibition and shed light on the therapeutic potential of LDH-A inhibitors in this tumour type.