Search

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. Consequently, targeting SIRT1 has emerged as a viable approach to treat cardiovascular diseases, leading to the identification of several SIRT1 activators derived from natural or synthetic sources. In this study, we developed anilinopyridine-based SIRT1 activators that displayed significantly greater potency in activating SIRT1 compared to the reference compound resveratrol, as demonstrated in enzymatic assays. In particular, compounds 8and 10, representative 6-aryl-2-anilinopyridine derivatives from this series, were further investigated pharmacologically and found to reduce myocardial damage caused by occlusion and subsequent reperfusion in vivo, confirming their cardioprotective properties. Notably, the cardioprotective effects of 8and 10were significantly superior to that of resveratrol. Significantly, compound 10emerged as the most potent among the tested compounds, demonstrating the ability to substantially decrease the size of the ischemic area at a dosage one hundred times lower (0.1 mg kg−1) than that of resveratrol/compound 1. These promising findings open avenues for expanding and optimizing this chemical class of potent SIRT1 activators as potential agents for cardioprotection.

In recent years, human dihydroorotate dehydrogenase inhibitors have been associated with acute myelogenous leukemia as well as studied as potent host targeting antivirals. Starting from MEDS433 (IC501.2 nM), we kept improving the structure–activity relationship of this class of compounds characterized by 2-hydroxypyrazolo[1,5-a]pyridine scaffold. Using an in silico/crystallography supported design, we identified compound 4(IC507.2 nM), characterized by the presence of a decorated aryloxyaryl moiety that replaced the biphenyl scaffold, with potent inhibition and pro-differentiating abilities on AML THP1 cells (EC5074 nM), superior to those of brequinar (EC50249 nM) and boosted when in combination with dipyridamole. Finally, compound 4has an extremely low cytotoxicity on non-AML cells as well as MEDS433; it has shown a significant antileukemic activity in vivo in a xenograft mouse model of AML.

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. Here, a new class of benzylpiperidine-based MAGL inhibitors was synthesized, leading to the identification of 13, which showed potent reversible and selective MAGL inhibition. Associated with MAGL overexpression and the prognostic role in pancreatic cancer, derivative 13showed antiproliferative activity and apoptosis induction, as well as the ability to reduce cell migration in primary pancreatic cancer cultures, and displayed a synergistic interaction with the chemotherapeutic drug gemcitabine. These results suggest that the class of benzylpiperidine-based MAGL inhibitors have potential as a new class of therapeutic agents and MAGL could play a role in pancreatic cancer.

AbstractATP citrate lyase (ACLY) is an important enzyme that catalyzes the conversion of citrate to acetyl-CoA in normal cells, facilitating the de novofatty acid synthesis. Lipids and fatty acids were found to be accumulated in different types of tumors, such as brain, breast, rectal and ovarian cancer, representing a great source of energy for cancer cell growth and metabolism. Since ACLY-mediated conversion of citrate to acetyl-CoA constitutes the basis for fatty acid synthesis, ACLY seems to be quite an unexplored and promising therapeutic target for anticancer drug design. A pharmacophore-based virtual screening (VS) protocol with the aid of hierarchical docking, consensus docking (CD), molecular dynamics (MD) simulations and ligand-protein binding free energy calculations led to the identification of compound VS1, which showed a moderate but promising inhibitory activity, demonstrating to be 2.5 times more potent than reference inhibitor 2-hydroxycitrate. These results validate the reliability of our VS workflow and pave the way for the design of novel and more potent ACLY inhibitors.Communicated by Ramaswamy H. Sarma

ABSTRACTIntroductionMonoacylglycerol lipase (MAGL) belongs to the endocannabinoid system and is responsible for the inactivation of endocannabinoid 2-arachidonoylglycerol. Importantly, it was found that MAGL degradation of lipids in cancer cells enhances the availability of free fatty acids for new cellular membrane formation and pro-oncogenic lipid modulators. The multifaceted role of MAGL has greatly stimulated the search for MAGL inhibitors, which could be effective to treat diseases, such as inflammation, neurodegeneration and cancer.Areas coveredThis review covers patents published since 2018 up to now, concerning new MAGL inhibitors and their potential therapeutic applications.Expert opinionIn the years 2018–2020, several well-known chemical scaffolds of MAGL inhibitors have been further optimized and developed and some new chemical classes have also been identified as MAGL inhibitors. Moreover, an increasing number of scientific publications covering MAGL inhibitors is focused on MAGL-specific positron emission tomography (PET) ligands. The numerous efforts of pharmaceutical companies and academic research groups finalized to find new potent MAGL inhibitors confirm that this research area is rapidly growing. Nevertheless, most of the patented compounds still belong to the large group of irreversible MAGL inhibitors, highlighting that the development of reversible MAGL inhibitors is still an unmet pharmaceutical need.

The Mg2+-dependent Mycobacterium tuberculosissalicylate synthase (MbtI) is a key enzyme involved in the biosynthesis of siderophores. Because iron is essential for the survival and pathogenicity of the microorganism, this protein constitutes an attractive target for antitubercular therapy, also considering the absence of homologous enzymes in mammals. An extension of the structure–activity relationships of our furan-based candidates allowed us to disclose the most potent competitive inhibitor known to date (10, Ki= 4 μM), which also proved effective on mycobacterial cultures. By structural studies, we characterized its unexpected Mg2+-independent binding mode. We also investigated the role of the Mg2+cofactor in catalysis, analyzing the first crystal structure of the MbtI–Mg2+–salicylate ternary complex. Overall, these results pave the way for the development of novel antituberculars through the rational design of improved MbtI inhibitors.

A surface extract of the aerial parts of Salvia tingitanaafforded a nor-sesterterpenoid (1) and eight new sesterterpenoids (2–̵9), along with five known sesterterpenoids, five labdane and one abietane diterpenoid, one sesquiterpenoid, and four flavonoids. The structures of the new compounds were established by 1D and 2D NMR spectroscopy, HRESIMS, and VCD data and Mosher’s esters analysis. The antimicrobial activity of compounds was evaluated against 30 human pathogens including 27 clinical strains and three isolates of marine origin for their possible implications on human health. The methyl ester of salvileucolide (10), salvileucolide-6,23-lactone (11), sclareol (15), and manool (17) were the most active against Gram-positive bacteria. The compounds were also tested for the inhibition of ATP production in purified mammalian rod outer segments. Terpenoids 10, 11, 15, and 17inhibited ATP production, while only 17inhibited also ATP hydrolysis. Molecular modeling studies confirmed the capacity of 17to interact with mammalian ATP synthase. A significant reduction of ATP production in the presence of 17was observed in Enterococcus faecalisand E. faeciumisolates.

Background: Molecular docking is probably the most popular and profitable approach in computer-aided drug design, being the staple technique for predicting the binding mode of bioactive compounds and for performing receptor-based virtual screening studies. The growing attention received by docking, as well as the need for improving its reliability in pose prediction and virtual screening performance, has led to the development of a wide plethora of new docking algorithms and scoring functions. Nevertheless, it is unlikely to identify a single procedure outperforming the other ones in terms of reliability and accuracy or demonstrating to be generally suitable for all kinds of protein targets. Methods: In this context, consensus docking approaches are taking hold in computer-aided drug design. These computational protocols consist in docking ligands using multiple docking methods and then comparing the binding poses predicted for the same ligand by the different methods. This analysis is usually carried out calculating the root-mean-square deviation among the different docking results obtained for each ligand, in order to identify the number of docking methods producing the same binding pose. Results: The consensus docking approaches demonstrated to improve the quality of docking and virtual screening results compared to the single docking methods. From a qualitative point of view, the improvement in pose prediction accuracy was obtained by prioritizing ligand binding poses produced by a high number of docking methods, whereas with regards to virtual screening studies, high hit rates were obtained by prioritizing the compounds showing a high level of pose consensus. Conclusion: In this review, we provide an overview of the results obtained from the performance assessment of various consensus docking protocols and we illustrate successful case studies where consensus docking has been applied in virtual screening studies.

Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.

Monoacylglycerol lipase (MAGL) is the enzyme degrading the endocannabinoid 2-arachidonoylglycerol, and it is involved in several physiological and pathological processes. The therapeutic potential of MAGL is linked to several diseases, including cancer. The development of MAGL inhibitors has been greatly limited by the side effects associated with the prolonged MAGL inactivation. Importantly, it could be preferable to use reversible MAGL inhibitors in vivo, but nowadays only few reversible compounds have been developed. In the present study, structural optimization of a previously developed class of MAGL inhibitors led to the identification of compound 23, which proved to be a very potent reversible MAGL inhibitor (IC50= 80 nM), selective for MAGL over the other main components of the endocannabinoid system, endowed of a promising antiproliferative activity in a series of cancer cell lines and able to block MAGL both in cell-based as well as in vivo assays.

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.mmvsl.it/wp/venompred2/), the new and improved version of our free of charge web tool for toxicological predictions, which now represents a powerful web-based platform for multifaceted and human-interpretable in silicotoxicity profiling of chemicals. VenomPred 2.0 presents an extended set of toxicity endpoints (androgenicity, skin irritation, eye irritation, and acute oral toxicity, in addition to the already available carcinogenicity, mutagenicity, hepatotoxicity, and estrogenicity) that can be evaluated through an exhaustive consensus prediction strategy based on multiple ML models. Moreover, we also implemented a new utility based on the Shapley Additive exPlanations (SHAP) method that allows human interpretable toxicological profiling of small molecules, highlighting the features that strongly contribute to the toxicological predictions in order to derive structural toxicophores.

Growing evidence indicates that transient receptor potential (TRP) channels contribute to different forms of pruritus. However, the endogenous mediators that cause itch through transient receptor potential channels signaling are poorly understood. In this study, we show that genetic deletion or pharmacological antagonism of TRPV4 attenuated itch in a mouse model of psoriasis induced by topical application of imiquimod. Human psoriatic lesions showed increased expression of several microRNAs, including the miR-203b-3p, which induced a calcium ion response in rodent dorsal root ganglion neurons and scratching behavior in mice through 5-HTR2B activation and the protein kinase C‒dependent phosphorylation of TRPV4. Computer simulation revealed that the miR-203b-3p core sequence (GUUAAGAA) that causes 5-HTR2B/TRPV4-dependent itch targets the extracellular side of 5-HTR2B by interacting with a portion of the receptor pocket consistent with its activation. Overall, we reveal the unconventional pathophysiological role of an extracellular microRNA that can behave as an itch promoter through 5-HTR2B and TRPV4.

Here, we present MolBook UNIPI, freely available and user-friendly software specifically designed for medicinal chemists as a powerful tool for the easy management of virtual libraries of chemical compounds. With MolBook UNIPI, it is possible to create, store, handle, and share molecular databases in a very simple and intuitive way. The software allows users to rapidly generate libraries of bioactive ligands, building blocks, or commercial compounds by either manually creating single molecules or automatically importing compounds from public databases and pre-existing libraries. MolBook UNIPI databases can be enriched with all kinds of data and can be filtered based on molecular structures or properties, allowing the desired molecules, along with their structures and features, to be easily accessible in just a few clicks. Moreover, new molecular properties and potential toxicological effects of compounds can be rapidly and reliably predicted. Notably, all of these functions can be easily mastered even by inexperienced users, with no prior cheminformatics knowledge or programming skills, which makes MolBook UNIPI an invaluable tool for medicinal chemists. MolBook UNIPI can be downloaded free of charge from the project web page https://molbook.farm.unipi.it/.

Five new diterpenes (1–5) and a megastigmane derivative (6) were isolated from the aerial parts of Euphorbia laurifolia, along with several known compounds. Their structures were elucidated by NMR, MS, and ECD and by chemical methods. A chemical proteomics drug affinity responsive target stability (DARTS) approach to investigate the lathyrane diterpene 1, laurifolioside, on its putative cellular target(s) was performed. Clathrin heavy chain 1, a protein mainly involved in selective uptake of proteins, viruses, and other macromolecules at the plasma membrane of cells, was identified as the major interaction partner of compound 1. The modulation of clathrin activity by 1was studied through microscopy, molecular docking, and molecular dynamics studies, suggesting a new activity of lathyrane diterpenes in the modulation of trafficking pathways.

Inhibitors of human lactate dehydrogenase 5 (hLDH5) are promising therapeutic agents against cancer. This enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. In this study, with the aim of identifying new hLDH5 inhibitors, a receptor‐based pharmacophore modeling approach has been tested and, in order to verify the reliability of the reported approach, the Gold and Platinum database from Asinex were filtered. The top‐ranked compounds were experimentally tested for their hLDH5 inhibition activity and enzymatic assays revealed that, among the ten selected compounds, two proved to inhibit the enzyme activity with Kivalues in the micromolar range (Ki=33.1–76.7 μM).