Uncovering the Potential of Lipid Drugs: A Focus on Transient Membrane Microdomain-targeted Lipid Therapeutics.

Membrane lipids are generally viewed as inert physical barriers, but many vital cellular processes greatly rely on the interaction with these structures, as expressed by the membrane hypothesis that explain the genesis of schizophrenia, Alzheimer's and autoimmune diseases, chronic fatigue or cancer. The concept that the cell membrane displays transient membrane microdomains with distinct lipid composition providing the basis for the development of selective lipid-targeted therapies, the membrane-lipid therapies (MLTs). In this concern, medicinal chemists may design therapeutically valuable compounds 1) with a higher affinity for the lipids in these microdomains to restore the normal physiological conditions, 2) that can directly or 3) indirectly (via enzyme inhibition/activation) replace damaged lipids or restore the regular lipid levels in the whole membrane or microdomain, 4) that alter the expression of genes related to lipid genesis/metabolism or 5) that modulate the pathways related to the membrane binding affinity of lipid-anchored proteins. In this context, this mini-review aims to explore the structural diversity and clinical applications of some of the main membrane and microdomain-targeted lipid drugs.

In silico design and in vitro assessment of anti-Helicobacter pylori compounds as potential small-molecule arginase inhibitors.

Related to a variety of gastrointestinal disorders ranging from gastric ulcer to gastric adenocarcinoma, the infection caused by the gram-negative bacteria Helicobacter pylori (H. pylori) poses as a great threat to human health; hence, the search for new treatments is a global priority. The H. pylori arginase (HPA) protein has been widely studied as one of the main virulence factors of this bacterium, being involved in the prevention of nitric oxide-mediated bacterial cell death, which is a central component of innate immunity. Given the growing need for the development of new drugs capable of combating the infection by H. pylori, the present work describes the search for new HPA inhibitors, using virtual screening techniques based on molecular docking followed by the evaluation of the proposed modes of interaction at the HPA active site. In vitro studies of minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC), followed by cytotoxicity activity in gastric adenocarcinoma and non-cancer cells, were performed. The results highlighted compounds 6, 11, and 13 as potential inhibitors of HPA; within these compounds, the results indicated 13 presented an improved activity toward H. pylori killing, with MIC and MBC both at 64 µg/mL. Moreover, compound 13 also presented a selectivity index of 8.3, thus being more selective for gastric adenocarcinoma cells compared to the commercial drug cisplatin. Overall, the present work demonstrates the search strategy based on in silico and in vitro techniques is able to support the rational design of new anti-H. pylori drugs.

Click ferrocenyl-erlotinib conjugates active against erlotinib-resistant non-small cell lung cancer cells in vitro.

Thanks to development of erlotinib and other target therapy drugs the lung cancer treatment have improved a lot in recent years. However, erlotinib-resistant lung cancer remains an unsolved clinical problem which demands for new therapeutics to be developed. Herein we report the synthesis of a library of 1,4- and 1,5-triazole ferrocenyl derivatives of erlotinib together with their anticancer activity studies against erlotinib-sensitive A549 and H1395 as well as erlotinib-resistant H1650 and H1975 cells. Studies showed that extend of anticancer activity is mainly related to the length of the spacer between the triazole and the ferrocenyl entity. Among the series of investigated compounds two isomers commonly bearing C(O)CH2CH2 spacer have shown superior to erlotinib activity against erlotinib-resistant H1650 and H1975 cells whereas compound with short methylene spacer devoid of any activity. In-depth biological studies for the most active compound showed differences in its mechanism of action in compare to erlotinib. The latter is known EGFR inhibitor whereas their ferrocenyl congener exerts anticancer activity mainly as ROS-inducer which activates mitochondrial pathway of apoptosis in cancer cells. However, docking studies suggested that the most active compound can also binds to the active site of EGFR TK in a similar way as erlotinib.

Synthesis, biological evaluation and molecular docking studies of novel 1,2,3-triazole-quinazolines as antiproliferative agents displaying ERK inhibitory activity.

ERK1/2 inhibitors have attracted special attention concerning the ability of circumventing cases of innate or log-term acquired resistance to RAF and MEK kinase inhibitors. Based on the 4-aminoquinazoline pharmacophore of kinases, herein we describe the synthesis of 4-aminoquinazoline derivatives bearing a 1,2,3-triazole stable core to bridge different aromatic and heterocyclic rings using copper-catalysed azide-alkyne cycloaddition reaction (CuAAC) as a Click Chemistry strategy. The initial screening of twelve derivatives in tumoral cells (CAL-27, HN13, HGC-27, and BT-20) revealed that the most active in BT-20 cells (25a, IC50 24.6 µM and a SI of 3.25) contains a more polar side chain (sulfone). Furthermore, compound 25a promoted a significant release of lactate dehydrogenase (LDH), suggesting the induction of cell death by necrosis. In addition, this compound induced G0/G1 stalling in BT-20 cells, which was accompanied by a decrease in the S phase. Western blot analysis of the levels of p-STAT3, p-ERK, PARP, p53 and cleaved caspase-3 revealed p-ERK1/2 and p-STA3 were drastically decreased in BT-20 cells under 25a incubation, suggesting the involvement of these two kinases in the mechanisms underlying 25a-induced cell cycle arrest, besides loss of proliferation and viability of the breast cancer cell. Molecular docking simulations using the ERK-ulixertinib crystallographic complex showed compound 25a could potentially compete with ATP for binding to ERK in a slightly higher affinity than the reference ERK1/2 inhibitor. Further in silico analyses showed comparable toxicity and pharmacokinetic profiles for compound 25a in relation to ulixertinib.

Synthesis and biological evaluation of 2'-Aminochalcone: A multi-target approach to find drug candidates to treat Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative process that compromises cognitive functions. The physiopathology of AD is multifactorial and is mainly supported by the cholinergic and amyloid hypotheses, which allows the identification the fundamental role of some markers, such as the enzymes acetylcholinesterase (AChE) and ß-secretase (BACE-1), and the ß-amyloid peptide (Aß). In this work, we prepared a series of chalcones and 2'-aminochalcones, which were tested against AChE and BACE-1 enzymes and on the aggregation of Aß. All compounds inhibited AChE activity with different potencies. We have found that the majority of chalcones having the amino group are able to inhibit BACE-1, which was not observed for chalcones without this group. The most active compound is the one derived from 2,3-dichlorobenzaldeyde, having an IC50 value of 2.71 µM. A molecular docking study supported this result, showing a good interaction of the amino group with aspartic acid residues of the catalytic diade of BACE-1. Thioflavin-T fluorescence emission is reduced in 30 - 40%, when Aß42 is incubated in the presence of some chalcones under aggregation conditions. In vitro cytotoxicity and in silico prediction of pharmacokinetic properties were also conducted in this study.

1,2,3-Triazole tethered 2-mercaptobenzimidazole derivatives: design, synthesis and molecular assessment toward C6 glioma cell line.

Aim: Glioblastoma multiforme (GBM) is an aggressive cancer with very limited clinical therapies. Herein, we have designed novel mercaptobenzimidazole derivatives (1-7) as multitarget antineoplastic drugs and assessed their antiproliferative profiles on an experimental model for GBM, the C6 glioma line. Results: The target compounds were synthesized in few steps with reasonable yields (33-90%). Compounds 1 (∼18 µM) and 4 (∼20 µM) showed dose-dependent antiproliferative effects on C6 glioma and significantly increased early apoptosis, but only 4 disrupted the cell cycle progression and did not induce autophagy. Docking simulations suggested these compounds as dual kinase and colchicine binding site inhibitors. Conclusion: In spite of the limited selective toxicity, 4 hold the potential to be further optimized for the treatment of GBM.

Insights into the Design of Inhibitors of the Urease Enzyme - A Major Target for the Treatment of Helicobacter pylori Infections.

Expressed by a variety of plants, fungi and bacteria, the urease enzyme is directly associated with the virulence factor of many bacteria, including Helicobacter pylori, a gram-negative bacterium related to several gastrointestinal diseases and responsible for one of the most frequent bacterial infections throughout the world. The Helicobacter pylori Urease (HPU) is a nickel-dependent metalloenzyme expressed in response to the environmental stress caused by the acidic pH of the stomach. The enzyme promotes the increase of gastric pH through acid neutralization by the products of urea hydrolysis, then critically contributing to the colonization and pathogenesis of the microorganism. At the same time, standard treatments for Helicobacter pylori infections have limitations such as the increasing bacterial resistance to the antibiotics used in the clinical practice. As a strategy for the development of novel treatments, urease inhibitors have proved to be promising, with a wide range of chemical compounds, including natural, synthetic and semisynthetic products to be researched and potentially developed as new drugs. In this context, this review highlights the advances in the field of HPU inhibition, presenting and discussing the basis for the research of new molecules aiming at the identification of more efficient therapeutic entities.

Structural basis for the design of allosteric inhibitors of the Aurora kinase A enzyme in the cancer chemotherapy.

Aurora kinases are essential enzymes for the control of cell cycle. The specific role of aurora kinase A (AURKA) is the regulation of spindle assembly and stability by promoting centrosome maturation and separation. Because AURKA is an essential protein for the normal occurrence of the cycle, mutations and deregulations in the activities of this protein are associated with several cancers. The kinase activity of AURKA is controlled by autocatalytic phosphorylation, which is facilitated after binding to a regulator protein, the Target Protein for Xenopuskinesin-like protein 2 (TPX2). SCOPE OF REVIEW: This review highlights the physiological and pathophysiological properties of AURKA, the structure of the AURKA/TPX2 complex and the main structural features that can be explored for the design of selective AURKA inhibitors. MAJOR CONCLUSIONS: The design of selective AURKA inhibitors remains as a challenge as most of the currently available inhibitors target only the ATP binding cleft and are nonselective among kinases. However, by exploring the inactive form of the kinase, researchers get access to an adjacent hydrophobic pocket, allowing the design of more selective inhibitors. Additionally, the possibility of designing potent allosteric AURKA inhibitors look very promising from the clinical perspective, since it tends to yield the most selective class of compounds. GENERAL SIGNIFICANCE: Herein we detailed the binding modes of the most selective AURKA inhibitors currently reported. We believe this will aid researchers in defining the structural patterns necessary for selective AURKA inhibition, guiding the design of more potent compounds to be therapeutically explored in cancer patients.

Search for Potential Inducible Nitric Oxide Synthase Inhibitors with Favorable ADMET Profiles for the Therapy of Helicobacter pylori Infections.

BACKGROUND: Helicobacter pylori is a gram-negative bacterium related to chronic gastritis, peptic ulcer and gastric carcinoma. During its infection process, promotes excessive inflammatory response, increasing the release of reactive species and inducing the production of pro-inflammatory mediators. Inducible Nitric Oxide Synthase (iNOS) plays a crucial role in the gastric carcinogenesis process and a key mediator of inflammation and host defense systems, which is expressed in macrophages induced by inflammatory stimuli. In chronic diseases such as Helicobacter pylori infections, the overproduction of NO due to the prolonged induction of iNOS is of major concern. OBJECTIVES: In this sense, the search for potential iNOS inhibitors is a valuable strategy in the overall process of Helicobacter pylori pathogeny. METHODS: In silico techniques were applied in the search of interesting compounds against Inducible Nitric Oxide Synthase enzyme in a chemical space of natural products and derivatives from the Analyticon Discovery databases. RESULTS: The five compounds with the best iNOS inhibition profile were selected for activity and toxicity predictions. Compound 9 (CAS 88198-99-6) displayed significant potential for iNOS inhibition, forming hydrogen bonds with residues from the active site and an ionic interaction with heme. This compound also displayed good bioavailability and absence of toxicity/or from its probable metabolites. CONCLUSION: The top-ranked compounds from the virtual screening workflow show promising results regarding the iNOS inhibition profile. The results evidenced the importance of the ionic bonding during docking selection, playing a crucial role in binding and positioning during ligand-target selection for iNOS.

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 20h and 20e, with an anti-proliferative effects, achieving IC50 values of about half that of the IC50 of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the 20e and 20h compounds induced cell cycle arrest in the G2/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to Caenorhabditis elegans.

Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure.

BACKGROUND: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. METHODS: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. RESULTS: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). CONCLUSIONS: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aß levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

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. The fact that some alkylphospholipids (e.g. edelfosine: 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) selectively induce the apoptotic death of cancer cells by recruiting Fas death receptors and the downstream signaling molecules into clusters of lipid rafts suggests these potential drug targets deserve a more in-depth investigation. Herein, we review the structure of lipid rafts, their role in apoptotic signaling pathways and their potential role as drug targets for the treatment of cancer.

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. These actions support tumor growth and development. It has been suggested that the inhibition of ecto-5'-NT results in lower extracellular concentrations of adenosine within the tumor microenvironment, which would directly affect cancer cells and render malignant cells more susceptible to host defense systems. Such mechanisms are proposed to represent promising new targets for cancer therapy. The aim of this review is to explore the biochemical and structural features of ecto-5'-NT, including a brief analysis of its active site by molecular modeling, as a means of evaluating whether the inhibition of this enzyme does indeed represent a feasible strategy for treating cancer. Known inhibitors and possible prototypes that could be used to target ecto-5'-NT during cancer therapy are also discussed.

New insights into the chemistry and antioxidant activity of coumarins.

Coumarins are considered to be privileged structures due to their broad range of biological properties, including anticoagulant, anti-neurodegenerative, antioxidant, anticancer and antimicrobial activities. These interesting properties of coumarins can be ascribed to the chemical attributes of the 2H-chromen-2-one core; its aromatic ring can establish a series of hydrophobic, π-π, CH-π and cation-π interactions, and the two oxygen atoms in the lactone ring may hydrogen-bond to a series of amino acid residues in different classes of enzymes and receptors. Additionally, the double bond in the lactone helps to make the entire system planar, allows charge delocalization between the carbonyl group of the lactone and the aromatic ring and confers the characteristic fluorescence of this class of compounds, which can be explained by their preventing the trans-cis transformation of the double bond under ultraviolet (UV) irradiation. It is the possibility of radical delocalization in the 2H-chromen-2-one nucleus that makes most of the coumarins good antioxidants by acting as free radical scavengers, although some coumarins (mainly hydroxycoumarins) may also prevent the formation of free radicals by chelating metal ions. In this review, we provide a systematic analysis of the most important aspects surrounding the development of coumarins as antioxidants. Our analysis includes the synthesis of some complex antioxidant coumarins, strategies for structural modification to improve their antioxidant activities, qualitative/ quantitative structure-antioxidant relationships studies and the main in vitro assays used to evaluate their antioxidant properties.

Search for a platelet-activating factor receptor in the Trypanosoma cruzi proteome: a potential target for Chagas disease chemotherapy

Chagas disease (CD) causes the highest burden of parasitic diseases in the Western Hemisphere and is therefore a priority for drug research and development. Platelet-activating factor (PAF) causes the CD parasite Trypanosoma cruzi to differentiate, which suggests that the parasite may express PAF receptors. Here, we explored the T. cruzi proteome for PAF receptor-like proteins. From a total of 23,000 protein sequences, we identified 29 hypothetical proteins that are predicted to have seven transmembrane domains (TMDs), which is the main characteristic of the G protein-coupled receptors (GPCRs), including the PAF receptor. The TMDs of these sequences were independently aligned with domains from 25 animal PAF receptors and the sequences were analysed for conserved residues. The conservation score mean values for the TMDs of the hypothetical proteins ranged from 31.7-44.1 percent, which suggests that if the putative T. cruzi PAF receptor is among the sequences identified, the TMDs are not highly conserved. These results suggest that T. cruzi contains several GPCR-like proteins and that one of these GPCRs may be a PAF receptor. Future studies may further validate the PAF receptor as a target for CD chemotherapy.

Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy.

In this work, we have used molecular dynamics, density functional theory, virtual screening, ADMET predictions, and molecular interaction field studies to design and propose eight novel potential inhibitors of CDK2. The eight molecules proposed showed interesting structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for the treatment of cancer. The parameters related to the Rule of Five were calculated, and only one of the molecules violated more than one parameter. One of the proposals and one of the drug-like compounds selected by virtual screening indicated to be promising candidates for CDK2-based cancer therapy.

Acidentes com os medicamentos: como minimizá-los? / Medication misadventures: how to minimize them?

Esta revisão apresenta e discute os problemas relacionados aos acidentes envolvendo medicamentos, da prescrição ao uso, as etapas críticas e estratégias para minimizá-los. Os medicamentos são reconhecidos, em sua maioria, como eficazes, minimizando sofrimentos e curando pessoas, porém, quando utilizados de maneira inadequada podem representar riscos à saúde. Portanto, os serviços de saúde devem priorizar a segurança do usuário, visando à redução dos acidentes previsíveis com os medicamentos. Acidentes com medicamentos são todos os incidentes, problemas ou insucessos, previsíveis ou não, produzidos ou não por erro, conseqüência ou não de imperícia, imprudência ou negligência, que ocorrem durante o processo de utilização dos medicamentos, causem estes eventos danos, ou não, ao paciente. Podem ser classificados como "reações adversas" e "erros de medicação". Considerando que maioria dos erros de medicação ocorre no estágio de prescrição do medicamento, a adoção de sistemas de prescrição eletrônica de medicamentos, com suporte à decisão clínica, pode reduzir significativamente os eventos adversos relacionados aos medicamentos, melhorando a qualidade e a eficiência do tratamento farmacológico, com redução de custos para o sistema de saúde.

The readiness of the medicines for the prevention and combat to diseases makes the medicine therapy the main instrument of medical practice in the individuals' treatment for recovery of health. Although they are recognized as effective, minimizing suffering and curing people, they can also represent serious risks for health, especially when used in an inadequate way. Consequently, the user's safety in the process of using medicines, seeking the reduction of damages and predictable injuries, should be a priority in the health services. Considering that more than half of all of the medication mistakes happen in the apprenticeship of prescription of medicine, the adoption of mechanisms that alerts the doctor during the prescription can have a positive impact in the reduction of the total number of adverse events associated to medicines and in the expenses with the health service. The adoption of electronic systems in medicine prescription as a support to the clinical decision can significantly reduce the occurrence of adverse events related to medicines, improving the quality and efficiency of the pharmacological treatment.