α-Ketoisocaproic Acid Disrupts Mitochondrial Bioenergetics in the Brain of Neonate Rats: Molecular Modeling Studies of α-ketoglutarate Dehydrogenase Subunits Inhibition.

Brain accumulation of the branched-chain α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) occurs in maple syrup urine disease (MSUD), an inherited intoxicating metabolic disorder caused by defects of the branched-chain α-keto acid dehydrogenase complex. Patients commonly suffer life-threatening acute encephalopathy in the newborn period and develop chronic neurological sequelae of still undefined pathogenesis. Therefore, this work investigated the in vitro influence of pathological concentrations of KIC (5 mM), KMV (1 mM), and KIV (1 mM) on mitochondrial bioenergetics in the cerebral cortex of neonate (one-day-old) rats.

Antitumoral activity of different Amaryllidaceae alkaloids: In vitro and in silico assays.

Ethnopharmacology Relevance: The plants of Amaryllidaceae family, such as Amaryllis belladonna L., have been used as herbal remedies for thousands of years to address various disorders, including diseases that might today be identified as cancer.

Aim Of The Study: The objective of this work was to evaluate the potential of three Amaryllidaceae alkaloids against four cancer cell lines.

LaSOM 335, active against bladder cancer cells, interferes with Let-60 (hRas) and reduces CD73 expression/activity.

Bladder cancer is the fourth most common malignancy in men. It can present along the entire continuum of severity, from mild to well-differentiated disease to extremely malignant tumors with low survival rates. Human RAS genes are the most frequently mutated oncogenes in human cancers, and the critical role of aberrant Ras protein function in carcinogenesis is well established.

Prediction of ADMET/Drug-likeness Properties of Bioactive Phloroglucinols from Genus.

Background: Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section).

Targeting ecto-5'-nucleotidase: A comprehensive review into small molecule inhibitors and expression modulators.

The purinergic signaling has drawn attention from academia and more recently from pharmaceutical industries as a potential therapeutic route for cancer treatment, since ATP may act as chemotactic agent and possess in vitro antineoplastic activity. On the other way, adenosine, produced in extracellular medium by ecto-5'-NT, acts as immunosuppressor and is related to neoangiogenesis, vasculogenesis and evasion to the immune system. Consequently, inhibitors of ecto-5'-NT may prevent tumor progression, reducing adenosine concentrations, preventing escape from the host's immune system and slowing cancer's growth.

The Role of Alternative Toxicological Trials in Drug Discovery Programs. The Case of and Other Methods.

The discovery of a new drug requires over a billion dollars and around 12 years of research efforts, and toxicity is the leading reason for the failure to approve candidate drugs. Many alternative methods have been validated to detect toxicity as early as possible to diminish the waste of resources and efforts in medicinal chemistry research, and in vivo alternative methods are especially valuable for the amount of information they can provide at little cost and in a short time. In this work, we present a review of the literature published between the years 2000 and 2021 on in vivo alternative methods of toxicity screening employed in medicinal chemistry, which we believe will be useful because, in addition to shortening the research time, these studies provide much additional information aside from the toxicity of drug candidate compounds.

Exploring the N1 Position of Biginelli Compounds: New Insights and Trends for Chemical Diversity Generation of Bioactive Derivatives.

Dihydropyrimidinones (DHPMs) are heterocycles obtained by the multicomponent Biginelli reaction. Recently, new synthetic protocols have allowed us to explore functionalisation at less explored positions of DHPMs, such as the N1 position. In this context, a full literature survey of N1- substituted DHPMs was performed.

New insights into cytotoxic mechanisms of bozepinib against glioblastoma.

Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults and the current treatments only have a modest effect on patient survival. Recent studies show that bozepinib (BZP), a purine derivative, has potential applications in cancer treatment. The aim of this study was to evaluate the effect of BZP against GBM cells, specially concerning the purinergic system.

Discovery, development, chemical diversity and design of isoxazoline-based insecticides.

Isoxazoline is a 5-membered heterocycle present in the active compounds of many commercial veterinary anti-ectoparasitic products. The molecular target of isoxazolines is the inhibition of GABA-gated chloride channels in insects. These facts have inspired the use of the isoxazoline scaffold in the design of novel insecticide compounds.

Diagnostic significance of C-reactive protein and hematological parameters in acute toxoplasmosis.

Abstract: Toxoplasmosis is a zoonosis caused by , which can be acquired by oral contact and may cause severe health problems especially for pregnant (congenital toxoplasmosis) and immunocompromised patients. This study aimed to verify the diagnostic significance of hematological parameters and C-reactive protein (CRP) for toxoplasmosis acute detection. A case-control study was carried out between December 2017 and May 2018, in samples of convenience independent of age and sex.

Natural and synthetic coumarins as antileishmanial agents: A review.

The neglected tropical disease leishmaniasis is still a major public health problem that affects millions of people worldwide. Related to poor-living conditions, this vector-borne disease presents multiple clinical manifestations - from asymptomatic to systemic conditions. The protozoans of the genus Leishmania are the etiologic agents transmitted through the bite of sandflies, the main vectors.

Geo-Measures: A PyMOL plugin for protein structure ensembles analysis.

Although molecular dynamics encompasses several applications, studies focusing on biomolecular systems are central issues of this research area. Such simulations require the generation of trajectory files, which provide a path for the analysis and interpretation of results with biological significance. However, although several programs have been developed in Python language for the analyses of molecular dynamics (MD) trajectories, they usually require some knowledge of programming languages in order to write or run the scripts using command lines, which certainly hinders the access of MD simulations to many scientists with the necessary biological background to interpret their results.

New pharmacological findings linked to biphenyl DHPMs, kinesin Eg5 ligands: anticancer and antioxidant effects.

Dihydropyrimidin-2-thiones (DHPMs) are a class of heterocyclic compound which have been intensively investigated mainly due to their anticancer activity as kinesin Eg5 inhibitors. A library of N1 aryl substituted DHPMs were tested against glioma and bladder cancer cell lines. Quantitative structure-activity relationship (QSAR) investigation was performed in order to identify key elements of DHPMs linked with their antiproliferative effect.

Novel coumarins active against Trypanosoma cruzi and toxicity assessment using the animal model Caenorhabditis elegans.

Background: Chagas disease (CD) is a tropical parasitic disease. Although the number of people infected is very high, the only drugs available to treat CD, nifurtimox (Nfx) and benznidazole, are highly toxic, particularly in the chronic stage of the disease. Coumarins are a large class of compounds that display a wide range of interesting biological properties, such as antiparasitic.

Targeting pteridine reductase 1 and dihydrofolate reductase: the old is a new trend for leishmaniasis drug discovery.

Leishmaniasis is one of the major neglected tropical diseases in the world and it is considered endemic in 88 countries. This disease is transmitted by a spp. infected sandfly and it may lead to cutaneous or systemic manifestations.

Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.

An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called and , with an anti-proliferative effects, achieving IC values of about half that of the IC of monastrol in both cell lines.

Beyond the "Lock and Key" Paradigm: Targeting Lipid Rafts to Induce the Selective Apoptosis of Cancer Cells.

For more than 40 years, the fluid mosaic model of cellular membranes has supported our vision of an inert lipid bilayer containing membrane protein receptors that are randomly hit by extracellular molecules to trigger intracellular signaling events. However, the notion that compartmentalized cholesterol- and sphingomyelin-rich membrane microdomains (known as lipid rafts) spatially arrange receptors and effectors to promote kinetically favorable interactions necessary for the signal transduction sounds much more realistic. Despite their assumed importance for the dynamics of ligand-receptor interactions, lipid rafts and biomembranes as a whole remain less explored than the other classes of biomolecules because of the higher variability and complexity of their membrane phases, which rarely provide the detailed atomic-level structural data in X-ray crystallography assays necessary for molecular modeling studies.

LiGRO: a graphical user interface for protein-ligand molecular dynamics.

To speed up the drug-discovery process, molecular dynamics (MD) calculations performed in GROMACS can be coupled to docking simulations for the post-screening analyses of large compound libraries. This requires generating the topology of the ligands in different software, some basic knowledge of Linux command lines, and a certain familiarity in handling the output files. LiGRO-the python-based graphical interface introduced here-was designed to overcome these protein-ligand parameterization challenges by allowing the graphical (non command line-based) control of GROMACS (MD and analysis), ACPYPE (ligand topology builder) and PLIP (protein-binder interactions monitor)-programs that can be used together to fully perform and analyze the outputs of complex MD simulations (including energy minimization and NVT/NPT equilibration).

In vitro and in silico Activity of Iridoids Against Leishmania amazonensis.

Background: Leishmaniasis reaches millions of people around the world. The control of the disease is difficult due to the restricted access to the diagnosis and medication, and low adherence to the treatment. Thus, more efficient drugs are needed and natural products are good alternatives.

Identification of a novel putative inhibitor of the Plasmodium falciparum purine nucleoside phosphorylase: exploring the purine salvage pathway to design new antimalarial drugs.

Malaria, a tropical parasitic disease caused by Plasmodium spp., continues to place a heavy social burden, with almost 200 million cases and more than 580,000 deaths per year. Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) can be targeted for antimalarial drug design since its inhibition kills malaria parasites both in vitro and in vivo.

Insights into Ecto-5'-Nucleotidase as a New Target for Cancer Therapy: A Medicinal Chemistry Study.

Ecto-5'-nucleotidase (ecto-5'-NT, 5'-NT, eN, CD73) is a membrane ecto-enzyme that is primarily responsible for the extracellular production of adenosine from AMP. Ecto-5'-NT is over expressed in various types of cancer cells, leading to elevated concentrations of adenosine in the tumor microenvironment. Adenosine has also been found to be important in cancer pathogenesis, showing strong immunosuppressive effects over antitumor T cells and macrophages and promoting neovascularization and cell adherence.