Exploring Biological Targets of Magnolol and Honokiol and their Nature-Inspired Synthetic Derivatives: In Silico Identification and Experimental Validation of Estrogen Receptors.

In this work, we describe the results of a computational investigation aimed at identifying potential biological targets of honokiol, magnolol and a series of synthetic prodrug derivatives obtained through esterification of the free hydroxyl groups. The ligand-based and structure-based analyses revealed that these compounds potentially interact with several biological targets, some of which are known while others are new. Honokiol, magnolol, and three of the newly synthesized derivatives may bind to estrogen receptors ERα and ERβ.

Cu-ZnO Embedded in a Polydopamine Shell for the Generation of Antibacterial Surgical Face Masks.

A new easy protocol to functionalize the middle layer of commercial surgical face masks (FMs) with Zn and Cu oxides is proposed in order to obtain antibacterial personal protective equipment. Zinc and copper oxides were synthesized embedded in a polydopamine (PDA) shell as potential antibacterial agents; they were analyzed by XRD and TEM, revealing, in all the cases, the formation of metal oxide nanoparticles (NPs). PDA is a natural polymer appreciated for its simple and rapid synthesis, biocompatibility, and high functionalization; it is used in this work as an organic matrix that, in addition to stabilizing NPs, also acts as a diluent in the functionalization step, decreasing the metal loading on the polypropylene (PP) surface.

Searching for Novel HDAC6/Hsp90 Dual Inhibitors with Anti-Prostate Cancer Activity: In Silico Screening and In Vitro Evaluation.

Prostate cancer (PCA) is one of the most prevalent types of male cancers. While current treatments for early-stage PCA are available, their efficacy is limited in advanced PCA, mainly due to drug resistance or low efficacy. In this context, novel valuable therapeutic opportunities may arise from the combined inhibition of histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90).

Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction.

Tauopathies such as Alzheimer's disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau's pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons.

Loss of calpain 3 dysregulates store-operated calcium entry and its exercise response in mice.

Limb-Girdle Muscular Dystrophy 2A (LGMD2A) is caused by mutations in the gene encoding Calpain 3, a skeletal-muscle specific, Ca-dependent protease. Localization of Calpain 3 within the triad suggests it contributes to Ca homeostasis. Through live-cell Ca measurements, muscle mechanics, immunofluorescence, and electron microscopy (EM) in deficient (C3KO) and wildtype (WT) mice, we determined if loss of Calpain 3 altered Store-Operated Calcium Entry (SOCE) activity.

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients.

Trends and Applications in Computationally Driven Drug Repurposing.

Drug repurposing is a widely used approach originally developed to aid in the identification of new uses of already existing drugs outside the scope of the original medical indication [...

Diaphragm Fatigue in SMNΔ7 Mice and Its Molecular Determinants: An Underestimated Issue.

Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of spinal motor neurons leading to muscle weakness and respiratory failure. Mitochondrial dysfunctions are found in the skeletal muscle of patients with SMA. For obvious ethical reasons, the diaphragm muscle is poorly studied, notwithstanding the very important role that respiratory involvement plays in SMA mortality.

Electron Microscopy (EM) Analysis of Collagen Fibers in the Peri-Implant Soft Tissues around Two Different Abutments.

The design of the implant prosthesis-abutment complex appears crucial for shaping healthy and stable peri-implant soft tissues. The aim of the present animal study was to compare two implants with different healing abutment geometries: a concave design (TEST) and a straight one (CTRL). Transmission electron microscopy (TEM) was used to quantify the three-dimensional topography and morphological properties of collagen at nanoscale resolution.

Discovery of potent pyrrolo-pyrimidine and purine HDAC inhibitors for the treatment of advanced prostate cancer.

The development of drugs for the treatment of advanced prostate cancer (PCA) remains a challenging task. In this study we have designed, synthesized and tested twenty-nine novel HDAC inhibitors based on three different zinc binding groups (trifluoromethyloxadiazole, hydroxamic acid, and 2-mercaptoacetamide). These warheads were conveniently tethered to variously substituted phenyl linkers and decorated with differently substituted pyrrolo-pyrimidine and purine cap groups.

Primary Hyperparathyroidism overlapping with Multiple Sclerosis: a catastrophic marriage.

Primary hyperparathyroidism (PHPT) often leads to neurological or psychiatric disorders, thus mimicking different diseases. Here we present a 77-years old man visited in the Emergency Department complaining for fatigue, multiple falls, nausea, anorexia, and constipation. Symptoms were rapidly worsening, and on admission he appeared sleepy, responsive to verbal stimulus, disoriented, dehydrated, unable to maintain upright position.

Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status.

Tau is a protein characterized by large structural portions displaying extended conformational changes. Unfortunately, the accumulation of this protein into toxic aggregates in neuronal cells leads to a number of severe pathologies, collectively named tauopathies. In the last decade, significant research advancements were achieved, including a better understanding of Tau structures and their implication in different tauopathies.

Identification of Promising Drug Candidates against Prostate Cancer through Computationally-Driven Drug Repurposing.

Prostate cancer (PC) is one of the most common types of cancer in males. Although early stages of PC are generally associated with favorable outcomes, advanced phases of the disease present a significantly poorer prognosis. Moreover, currently available therapeutic options for the treatment of PC are still limited, being mainly focused on androgen deprivation therapies and being characterized by low efficacy in patients.

Design, synthesis, biological evaluation and crystal structure determination of dual modulators of carbonic anhydrases and estrogen receptors.

Multi-target compounds have become increasingly important for the development of safer and more effective drug candidates. In this work, we devised a combined ligand-based and structure-based multi-target repurposing strategy and applied it to a series of hexahydrocyclopenta[c]quinoline compounds synthesized previously. The in silico analyses identified human Carbonic Anhydrases (hCA) and Estrogen Receptors (ER) as top scoring candidates for dual modulation.

Structure-activity exploration of a small-molecule allosteric inhibitor of T790M/L858R double mutant EGFR.

EGFR is a protein kinase whose aberrant activity is frequently involved in the development of non-small lung cancer (NSCLC) drug resistant forms. The allosteric inhibition of this enzyme is currently one among the most attractive approaches to design and develop anticancer drugs. In a previous study, we reported the identification of a hit compound acting as type III allosteric inhibitor of the L858R/T790M double mutant EGFR.

Development of machine learning classifiers to predict compound activity on prostate cancer cell lines.

Prostate cancer is the most common type of cancer in men. The disease presents good survival rates if treated at the early stages. However, the evolution of the disease in its most aggressive variant remains without effective therapeutic answers.

Constitutive assembly of Ca2+ entry units in soleus muscle from calsequestrin knockout mice.

Calcium (Ca2+) entry units (CEUs) are junctions within the I band of the sarcomere between stacks of sarcoplasmic reticulum (SR) cisternae and extensions of the transverse (T)-tubule. CEUs contain STIM1 and Orai1 proteins, the molecular machinery of store-operated Ca2+ entry (SOCE). In extensor digitorum longus (EDL) fibers of wild-type (WT) mice, CEUs transiently assemble during acute exercise and disassemble several hours thereafter.

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring.

Histone deacetylase (HDAC) inhibitors are highly involved in the regulation of many pharmacological responses, which results in anti-inflammatory and anti-cancer effects. In the present work, chemoinformatic analyses were performed to obtain two potent and selective aminotriazoloquinazoline-based HDAC6 inhibitors. We unexpectedly obtained an aminotriazole from a water-driven ring opening of the triazoloquinazoline scaffold.

Identification of potential biological targets of oxindole scaffolds via repositioning strategies.

Drug repurposing is an alternative strategy to traditional drug discovery that aims at predicting new uses for already existing drugs or clinical candidates. Drug repurposing has many advantages over traditional drug development, such as reduced attrition rates, time and costs. This is especially the case considering that most drugs investigated for repurposing have already been assessed for their safety in clinical trials.

Design and Synthesis of Hsp90 Inhibitors with B-Raf and PDHK1 Multi-Target Activity.

The design of multi-target ligands has become an innovative approach for the identification of effective therapeutic treatments against complex diseases, such as cancer. Recent studies have demonstrated that the combined inhibition of Hsp90 and B-Raf provides synergistic effects against several types of cancers. Moreover, it has been reported that PDHK1, which presents an ATP-binding pocket similar to that of Hsp90, plays an important role in tumor initiation, maintenance and progression, participating also to the senescence process induced by B-Raf oncogenic proteins.

Inhibitors of histone deacetylase 6 based on a novel 3-hydroxy-isoxazole zinc binding group.

Histone deacetylase 6 (HDAC6) is an established drug target for cancer treatment. Inhibitors of HDAC6 based on a hydroxamic acid zinc binding group (ZBG) are often associated with undesirable side effects. Herein, we describe the identification of HDAC6 inhibitors based on a completely new 3-hydroxy-isoxazole ZBG.