Design and pharmacological evaluation of Ibuprofen amides derivatives as dual FAAH/COX inhibitors

Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme responsible of the hydrolytic degradation of N-acylethanolamine endocannabinoids, such as the Arachidonoylethanolamide (anandamide, AEA), which it has been shown to alleviate pain and inflammation (1). In particular, the anti-nociceptive and anti-inflammatory effects of AEA could be enhanced by the simultaneous block of FAAH and COX enzymes (2). For this reason, several studies have been carried out in order to develop new FAAH/COX inhibitors (2). In 1997 it was reported that the NSAID ibuprofen inhibited FAAH, although with a modest potency (3), and successively the first dual inibhitor, the amide derivative of ibuprofen with a 2-amino-3-methylpyridine side chain (Ibu-AM5) was reported (4). -5). Benzylamides and piperazinoamides analogs of Ibuprofen have been also designed as less potent FAAH inhibitors than Ibu-AM5 (5). Here, I discuss the computational studies and the structure–activity relationships leading to the design, of novel Ibuprofen amide derivatives with a higher inhibition potency of FAAH and COX, which represent novel powerful anti-nociceptive agents

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor

Revealing the Supply Chain 4.0 Potential within the European Automotive Industry

Data Availability Statement: The datasets presented in this article are not readily available [the data are part of an ongoing study].With the rapid advancements in Information and Communication Technologies (ICT) and the widespread enthusiasm of both theoreticians and practitioners, the broader transition to Industry 4.0 (I4.0) in major industries appears imminent. This empirical study analyzes business data from 1140 automotive companies operating in Europe, utilizing various business intelligence platforms and employing decision tree analytics to establish connections between enablers, drivers, company size, and financial resources. The goal is to identify persistent barriers hindering the rational transition to Industry 4.0. The findings reveal an uneven transformation within the industry nexus. While larger companies possess the financial means to allocate collective intelligence, technical resources, and drive necessary for fulfilling I4.0 requirements, smaller members of the nexus lag behind despite their enthusiasm and intent. This imbalanced evolution poses a threat to the comprehensive transformation required for realizing all the benefits of Industry 4.0 within the sector. The primary discovery indicates that small to medium-sized enterprises do not exhibit the same rates of Industry 4.0 adoption, a lag highly correlated with their available financial and human resources for digital transition. The decision tree proposed in this study offers guidelines for achieving an Industry 4.0-compliant nexus. Given its diversity and substantial global impact, the case study from the automotive industry proves intriguing and may later be generalized to other sectors. The study’s outcome could empower engineering managers and researchers to implement, execute, and assess the impact of digital strategies based on the financial capabilities of industrial institutions.This research received no external funding

Structure-based virtual screening of novel natural alkaloid derivatives as potential binders of h-telo and c-myc DNA G-quadruplex conformations

Several ligands can bind to the non-canonical G-quadruplex DNA structures thereby stabilizing them. These molecules can act as effective anticancer agents by stabilizing the telomeric regions of DNA or by regulating oncogene expression. In order to better interact with the quartets of G-quadruplex structures, G-binders are generally characterized by a large aromatic core involved in pi-pi stacking. Some natural flexible cyclic molecules from Traditional Chinese Medicine have shown high binding affinity with G-quadruplex, such as berbamine and many other alkaloids. Using the structural information available on G-quadruplex structures, we performed a high throughput in silico screening of commercially available alkaloid derivative databases by means of a structure-based approach based on docking and molecular dynamics simulations against the human telomeric sequence d[AG(3)(T(2)AG(3))(3)] and the c-myc promoter structure. We identified 69 best hits reporting an improved theoretical binding affinity with respect to the active set. Among them, a berberine derivative, already known to remarkably inhibit telomerase activity, was related to a better theoretical affinity versus c-myc

Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target feature

3D GRID-based pharmacophore and Metadynamics approaches for the rational design of N-Methyl β-sheet breaker peptides as inhibitors of the Alzheimer's Aβ-amyloid fibrillogenesis

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the loss of the cognitive functions and dementia. Several scientific evidences report that a central role in the pathogenesis of AD is played by the brain deposition of insoluble aggregates of β-amyloid protein (Aβ) proteins, thus causing neuronal cell death [1]. For this reason, one of the promising approach is to inhibit the aggregation of Aβ peptides. Because Aβ is self-assembling, one possible strategy to prevent this process is to use short peptide fragments homologous to the full-length wild-type Aβ protein. From this consideration, several short synthetic peptides were designed as beta-sheet breakers (BSB) [2]. In particular, the pentapetide Ac-LPFFD-NH2 (iAβ5p) exhibited a certain capability to inhibit Aβ fibrillogenesis [3]. iAβ5p analogs [4] were, then, designed by introducing N-Methylation at the amide bond nitrogen were also promising BSB. Here, we describe the methodological approach, which combines 3D GRID-based pharmacophore peptide screening with Well-Tempered Metadynamics simulations aimed to the discovery of novel N-Methylated BSB. This approach led us to identify two promising, cell permeable, N-Methylated peptides that were further evaluated for their BSB properties showing a significant improvement of the fibrillogenesis inhibition with respect to the lead iAβ5p

Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In light of the urgent need to identify novel approaches to be used in the emergency phase, we have embarked on an exploratory campaign aimed at repurposing natural substances and clinically available drugs as potential anti-SARS-CoV2-2 agents by targeting viral proteins. Here we report on a strategy based on the virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike's protein receptor binding domain (RBD). By combining an in silico approach and molecular in vitro testing we have been able to identify several triterpenoid/steroidal agents that inhibit interaction of the Spike RBD with the carboxypeptidase domain of the Angiotensin Converting Enzyme (ACE2). In detail, we provide evidence that potential binding sites exist in the RBD of the SARS CoV-2 Spike protein and that occupancy of these pockets reduces the ability of the RBD to bind to the ACE2 consensus in vitro. Naturally occurring and clinically available triterpenoids such as glycyrrhetinic and oleanolic acids, as well as primary and secondary bile acids and their amidated derivatives such as glyco-ursodeoxycholic acid and semi-synthetic derivatives such as obeticholic acid reduces the RBD/ACE2 binding. In aggregate, these results might help to define novel approaches to COVID-19 based on SARS-CoV-2 entry inhibitors

Exploring the DNA2-PNA heterotriplex formation in targeting the Bcl-2 gene promoter: A structural insight by physico-chemical and microsecond-scale MD investigation

Peptide Nucleic Acids (PNAs) represent a promising tool for gene modulation in anticancer treatment. The uncharged peptidyl backbone and the resistance to chemical and enzymatic degradation make PNAs highly advantageous to form stable hybrid complexes with complementary DNA and RNA strands, providing higher stability than the corresponding natural analogues. Our and other groups’ research has successfully shown that tailored PNA sequences can effectively downregulate the expression of human oncogenes using antigene, antisense, or anti-miRNA approaches. Specifically, we identified a seven bases-long PNA sequence, complementary to the longer loop of the main G-quadruplex structure formed by the bcl2midG4 promoter sequence, capable of downregulating the expression of the antiapoptotic Bcl-2 protein and enhancing the anticancer activity of an oncolytic adenovirus. Here, we extended the length of the PNA probe with the aim of including the double-stranded Bcl-2 promoter among the targets of the PNA probe. Our investigation primarily focused on the structural aspects of the resulting DNA2-PNA heterotriplex that were determined by employing conventional and accelerated microsecond-scale molecular dynamics simulations and chemical-physical analysis. Additionally, we conducted preliminary biological experiments using cytotoxicity assays on human A549 and MDA-MB-436 adenocarcinoma cell lines, employing the oncolytic adenovirus delivery strategy

Evolving Indications for Tricuspid Valve Surgery

More attention has been paid to the mitral valve (MV) than the tricuspid valve (TV), and this relative paucity of data has led to confusion regarding the timing of TV surgery. We review the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines to identify areas of concordance (severe tricuspid regurgitation [TR] in a patient undergoing mitral valve surgery); discordance (less than severe TR but with markers for late TR recurrence such as pulmonary hypertension, a dilated TV annulus, atrial fibrillation, permanent transtricuspid pacing wires and others); and disagreement (surgery for primary TR). We provide our perspective from Northwestern University on these issues and where the guidelines are silent (TR in patients undergoing non-mitral valve operations). Finally, we review recent publications on the results of TV repair and replacement. Although there have been scant publications in the past, there have been more useful publications in recent years to guide our decision making