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1.
Genome Biol Evol ; 16(7)2024 07 03.
Article in English | MEDLINE | ID: mdl-38752399

ABSTRACT

Alternative splicing is the process of generating different mRNAs from the same primary transcript, which contributes to increase the transcriptome and proteome diversity. Abnormal splicing has been associated with the development of several diseases including cancer. Given that mutations and abnormal levels of the RIPK2 transcript and RIP-2 protein are frequent in tumors, and that RIP-2 modulates immune and inflammatory responses, we investigated alternative splicing events that result in partial deletions of the kinase domain at the N-terminus of RIP-2. We also investigated the structure and expression of the RIPK2 truncated variants and isoforms in different environments. In addition, we searched data throughout Supraprimates evolution that could support the biological importance of RIPK2 alternatively spliced products. We observed that human variants and isoforms were differentially regulated following temperature stress, and that the truncated transcript was more expressed than the long transcript in tumor samples. The inverse was found for the longer protein isoform. The truncated variant was also detected in chimpanzee, gorilla, hare, pika, mouse, rat, and tree shrew. The fact that the same variant has been preserved in mammals with divergence times up to 70 million years raises the hypothesis that it may have a functional significance.


Subject(s)
Alternative Splicing , Receptor-Interacting Protein Serine-Threonine Kinase 2 , Animals , Humans , Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism , Evolution, Molecular , Protein Isoforms/genetics , Mice , Neoplasms/genetics , Rats
2.
J Mol Model ; 28(9): 258, 2022 Aug 17.
Article in English | MEDLINE | ID: mdl-35978141

ABSTRACT

Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function. The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals. Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes. The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety. In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact peripherally with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking. The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular dynamics (MD) studies disclose that both complexes were stable by analyzing the RMSD (root mean square deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.


Subject(s)
Cannabinoids , Molecular Dynamics Simulation , Cannabinoids/chemistry , Cannabinoids/pharmacology , Humans , Molecular Docking Simulation , Zinc
3.
Front Mol Biosci ; 9: 836572, 2022.
Article in English | MEDLINE | ID: mdl-35720115

ABSTRACT

Skin Cancer (SC) is among the most common type of cancers worldwide. The search for SC therapeutics using molecular modeling strategies as well as considering natural plant-derived products seems to be a promising strategy. The phytochemical Rocaglamide A (Roc-A) and its derivatives rise as an interesting set of reference compounds due to their in vitro cytotoxic activity with SC cell lines. In view of this, we performed a hierarchical virtual screening study considering Roc-A and its derivatives, with the aim to find new chemical entities with potential activity against SC. For this, we selected 15 molecules (Roc-A and 14 derivatives) and initially used them in docking studies to predict their interactions with Checkpoint kinase 1 (Chk1) as a target for SC. This allowed us to compile and use them as a training set to build robust pharmacophore models, validated by Pearson's correlation (p) values and hierarchical cluster analysis (HCA), subsequentially submitted to prospective virtual screening using the Molport® database. Outputted compounds were then selected considering their similarities to Roc-A, followed by analyses of predicted toxicity and pharmacokinetic properties as well as of consensus molecular docking using three software. 10 promising compounds were selected and analyzed in terms of their properties and structural features and, also, considering their previous reports in literature. In this way, the 10 promising virtual hits found in this work may represent potential anti-SC agents and further investigations concerning their biological tests shall be conducted.

4.
Mini Rev Med Chem ; 20(9): 754-767, 2020.
Article in English | MEDLINE | ID: mdl-31686637

ABSTRACT

Parkinson's Disease (PD) is the second most common neurodegenerative disease in the elderly population, with a higher prevalence in men, independent of race and social class; it affects approximately 1.5 to 2.0% of the elderly population over 60 years and 4% for those over 80 years of age. PD is caused by the necrosis of dopaminergic neurons in the substantia nigra, which is the brain region responsible for the synthesis of the neurotransmitter dopamine (DA), resulting in its decrease in the synaptic cleft. The monoamine oxidase B (MAO-B) degrades dopamine, promoting the glutamate accumulation and oxidative stress with the release of free radicals, causing excitotoxicity. The PD symptoms are progressive physical limitations such as rigidity, bradykinesia, tremor, postural instability and disability in functional performance. Considering that there are no laboratory tests, biomarkers or imaging studies to confirm the disease, the diagnosis of PD is made by analyzing the motor features. There is no cure for PD, and the pharmacological treatment consists of a dopaminergic supplement with levodopa, COMT inhibitors, anticholinergics agents, dopaminergic agonists, and inhibitors of MAO-B, which basically aims to control the symptoms, enabling better functional mobility and increasing life expectancy of the treated PD patients. Due to the importance and increasing prevalence of PD in the world, this study reviews information on the pathophysiology, symptomatology as well as the most current and relevant treatments of PD patients.


Subject(s)
Dopamine Agents/therapeutic use , Parkinson Disease/drug therapy , Parkinson Disease/physiopathology , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Cholinergic Antagonists/therapeutic use , Dopamine Agonists/therapeutic use , Humans , Levodopa/therapeutic use , Life Expectancy , Monoamine Oxidase Inhibitors/therapeutic use , Oxidative Stress , Parkinson Disease/diagnosis
5.
J Mol Model ; 24(9): 225, 2018 Aug 07.
Article in English | MEDLINE | ID: mdl-30088101

ABSTRACT

Receptor-interacting protein kinase 2 (RIPK2) plays an essential role in autoimmune response and is suggested as a target for inflammatory diseases. A pharmacophore model was built from a dataset with ponatinib (template) and 18 RIPK2 inhibitors selected from BindingDB database. The pharmacophore model validation was performed by multiple linear regression (MLR). The statistical quality of the model was evaluated by the correlation coefficient (R), squared correlation coefficient (R2), explanatory variance (adjusted R2), standard error of estimate (SEE), and variance ratio (F). The best pharmacophore model has one aromatic group (LEU24 residue interaction) and two hydrogen bonding acceptor groups (MET98 and TYR97 residues interaction), having a score of 24.739 with 14 aligned inhibitors, which were used in virtual screening via ZincPharmer server and the ZINC database (selected in function of the RMSD value). We determined theoretical values of biological activity (logRA) by MLR, pharmacokinetic and toxicology properties, and made molecular docking studies comparing binding affinity (kcal/mol) results with the most active compound of the study (ponatinib) and WEHI-345. Nine compounds from the ZINC database show satisfactory results, yielding among those selected, the compound ZINC01540228, as the most promising RIPK2 inhibitor. After binding free energy calculations, the following molecular dynamics simulations showed that the receptor protein's backbone remained stable after the introduction of ligands.


Subject(s)
Molecular Docking Simulation , Molecular Dynamics Simulation , Receptor-Interacting Protein Serine-Threonine Kinase 2 , Cell Line , Drug Evaluation, Preclinical/methods , Humans , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/pathology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors , Receptor-Interacting Protein Serine-Threonine Kinase 2/chemistry , Receptor-Interacting Protein Serine-Threonine Kinase 2/metabolism
6.
Molecules ; 23(2)2018 Feb 18.
Article in English | MEDLINE | ID: mdl-29463017

ABSTRACT

The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built. Compounds were selected based on the available ZINC compounds database and in silico predictions of their pharmacokinetic, toxicity and potential biological activity. Molecular docking was performed to identify the probable interactions of the compounds as well as their binding affinity with RIPK2. The compounds were analyzed to ponatinib and WEHI-345, which also used as a control. At least one of the compounds exhibited suitable pharmacokinetic properties, low toxicity and an interesting binding affinity and high fitness compared with the crystallographic pose of WEHI-345 in complex with RIPK2. This compound also possessed suitable synthetic accessibility, rendering it a potential and very promising RIPK2 inhibitor to be further investigated in regards to different diseases, particularly inflammatory ones.


Subject(s)
Imidazoles/chemistry , Inflammation/drug therapy , Protein Kinase Inhibitors/chemistry , Pyridazines/chemistry , Receptor-Interacting Protein Serine-Threonine Kinase 2/antagonists & inhibitors , Crystallography, X-Ray , Humans , Imidazoles/therapeutic use , Molecular Docking Simulation , Protein Kinase Inhibitors/therapeutic use , Pyridazines/therapeutic use , Receptor-Interacting Protein Serine-Threonine Kinase 2/chemistry , Signal Transduction/drug effects , User-Computer Interface
7.
J Biomol Struct Dyn ; 36(2): 318-334, 2018 02.
Article in English | MEDLINE | ID: mdl-28027711

ABSTRACT

Human dipeptidyl peptidase IV (hDDP-IV) has a considerable importance in inactivation of glucagon-like peptide-1, which is related to type 2 diabetes. One approach for the treatment is the development of small hDDP-IV inhibitors. In order to design better inhibitors, we analyzed 5-(aminomethyl)-6-(2,4-dichlrophenyl)-2-(3,5-dimethoxyphenyl)pyrimidin-4-amine and a set of 24 molecules found in the BindingDB web database for model designing. The analysis of their molecular properties allowed the design of a multiple linear regression model for activity prediction. Their docking analysis allowed visualization of the interactions between the pharmacophore regions and hDDP-IV. After both analyses were performed, we proposed a set of nine molecules in order to predict their activity. Four of them displayed promising activity, and thus, had their docking performed, as well as, the pharmacokinetic and toxicological study. Two compounds from the proposed set showed suitable pharmacokinetic and toxicological characteristics, and therefore, they were considered promising for future synthesis and in vitro studies.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Hypoglycemic Agents/chemistry , Binding Sites , Dipeptidyl Peptidase 4/drug effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucagon-Like Peptide 1/chemistry , Humans , Hypoglycemic Agents/therapeutic use , Models, Molecular , Molecular Docking Simulation , Structure-Activity Relationship
8.
ChemMedChem ; 12(16): 1408-1416, 2017 08 22.
Article in English | MEDLINE | ID: mdl-28417566

ABSTRACT

Cannabis sativa withdrawal syndrome is characterized mainly by psychological symptoms. By using computational tools, the aim of this study was to propose drug candidates for treating withdrawal syndrome based on the natural ligands of the cannabinoid type 1 receptor (CB1). One compound in particular, 2-n-butyl-5-n-pentylbenzene-1,3-diol (ZINC1730183, also known as stemphol), showed positive predictions as a human CB1 ligand and for facile synthetic accessibility. Therefore, ZINC1730183 is a favorable candidate scaffold for further research into pharmacotherapeutic alternatives to treat C. sativa withdrawal syndrome.


Subject(s)
Cannabis/chemistry , Ligands , Receptor, Cannabinoid, CB1/metabolism , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Caco-2 Cells , Cannabis/metabolism , Cell Membrane Permeability/drug effects , Drug Design , Half-Life , Humans , Mice , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Receptor, Cannabinoid, CB2/metabolism , Resorcinols/chemistry , Resorcinols/pharmacokinetics , Resorcinols/pharmacology , Resorcinols/therapeutic use , Substance Withdrawal Syndrome/drug therapy , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology
9.
Eur J Pharmacol ; 783: 11-22, 2016 Jul 15.
Article in English | MEDLINE | ID: mdl-27118175

ABSTRACT

Diabetes mellitus is associated with reactive oxygen and nitrogen species accumulation. Behavioral stress increases nitric oxide production, which may trigger a massive impact on vascular cells and accelerate cardiovascular complications under oxidative stress conditions such as Diabetes. For this study, type-1 Diabetes mellitus was induced in Wistar rats by intraperitoneal injection of streptozotocin. After 28 days, cumulative concentration-response curves for angiotensin II were obtained in endothelium-intact carotid rings from diabetic rats that underwent to acute restraint stress for 3h. The contractile response evoked by angiotensin II was increased in carotid arteries from diabetic rats. Acute restraint stress did not alter angiotensin II-induced contraction in carotid arteries from normoglycaemic rats. However acute stress combined with Diabetes increased angiotensin II-induced contraction in carotid rings. Western blot experiments and the inhibition of nitric oxide synthases in functional assays showed that neuronal, endothelial and inducible nitric oxide synthase isoforms contribute to the increased formation of peroxynitrite and contractile hyperreactivity to angiotensin II in carotid rings from stressed diabetic rats. In summary, these findings suggest that the increased superoxide anion generation in carotid arteries from diabetic rats associated to the increased local nitric oxide synthases expression and activity induced by acute restrain stress were responsible for exacerbating the local formation of peroxynitrite and the contraction induced by angiotensin II.


Subject(s)
Angiotensin II/pharmacology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 1/metabolism , Nitric Oxide Synthase/metabolism , Nitric Oxide/biosynthesis , Peroxynitrous Acid/biosynthesis , Stress, Psychological/metabolism , Animals , Behavior, Animal/drug effects , Carotid Arteries/drug effects , Carotid Arteries/physiopathology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Experimental/psychology , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 1/psychology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Enzyme Activation/drug effects , Gene Expression Regulation, Enzymologic/drug effects , Male , Nitric Oxide Synthase/chemistry , Phenylephrine/pharmacology , Phosphorylation/drug effects , Rats , Rats, Wistar , Restraint, Physical , Vasoconstriction/drug effects
10.
Eur J Pharmacol ; 769: 143-6, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26548625

ABSTRACT

The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Proto-Oncogene Proteins/metabolism , Receptor, Angiotensin, Type 1/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Humans , Proto-Oncogene Mas
11.
Eur J Pharmacol ; 765: 503-16, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26387612

ABSTRACT

Hyperglycemia increases the generation of reactive oxygen species and affects systems that regulate the vascular tone including renin-angiotensin system. Stress could exacerbate intracellular oxidative stress during Diabetes upon the activation of angiotensin AT1/NADPH oxidase pathway, which contributes to the development of diabetic cardiovascular complications. For this study, type-I Diabetes was induced in Wistar rats by intraperitoneal injection of streptozotocin. 28 days after streptozotocin injection, the animals underwent to acute restraint stress for 3 h. Cumulative concentration-response curves for angiotensin II were obtained in carotid rings pre-treated or not with Nox or cyclooxygenase inhibitors. Nox1 or Nox4 expression and activity were assessed by Western blotting and lucigenin chemiluminescence, respectively. The role of Nox1 and Nox4 on reactive oxygen species generation was evaluated by flow cytometry and Amplex Red assays. Cyclooxygenases expression was assessed by real-time polymerase chain reaction. The contractile response evoked by angiotensin II was increased in diabetic rat carotid. Acute restraint stress increased this response in this vessel by mechanisms mediated by Nox4, whose local expression and activity in generating hydrogen peroxide are increased. The contractile hyperreactivity to angiotensin II in stressed diabetic rat carotid is also mediated by metabolites derived from cyclooxygenase-2, whose local expression is increased. Taken together, our findings suggest that acute restraint stress exacerbates the contractile hyperreactivity to angiotensin II in diabetic rat carotid by enhancing Nox4-driven generation of hydrogen peroxide, which evokes contractile tone by cyclooxygenases-dependent mechanisms. Finally, these findings highlight the harmful role played by acute stress in modulating diabetic vascular complications.


Subject(s)
Carotid Arteries/metabolism , Diabetes Mellitus, Type 1/metabolism , NADPH Oxidases/physiology , Stress, Psychological/metabolism , Acetylcholine/pharmacology , Angiotensin II/pharmacology , Animals , Carotid Arteries/drug effects , Dose-Response Relationship, Drug , Male , NADPH Oxidase 4 , Organ Culture Techniques , Rats , Rats, Wistar , Restraint, Physical/adverse effects , Vasoconstriction/drug effects , Vasoconstriction/physiology
12.
Eur J Pharmacol ; 764: 118-123, 2015 Oct 05.
Article in English | MEDLINE | ID: mdl-26142084

ABSTRACT

The important role played by aryl hydrocarbon receptor activation in the pathophysiology of atherosclerosis induced by cigarette smoke exposure has spurred the clinical interest in the development of aryl hydrocarbon receptor antagonists with atheroprotective efficacy. A few aryl hydrocarbon receptor antagonists were developed but the lack of structural information regarding the receptor ligand binding domain resulted in several limitations in the pharmacological properties of these compounds including partial agonism, allosterism, non-selectivity, cytotoxicity and susceptibility to bioactivation. These limitations make the progress of preclinical and clinical assays with the available aryl hydrocarbon receptor antagonists difficult. There is a great interest in developing pure, competitive, selective, nontoxic and resistant to bioactivation aryl hydrocarbon receptor antagonists. Current technology permits the development of pharmacologically ideal antagonists based on the chemical features of the aryl hydrocarbon receptor ligand binding domain. According to these characteristics, chlorinated derivatives of trans-stilbene meta-substituted with electrophilic aromatic directing groups would be effective prototypes for pure, competitive, selective, nontoxic and resistant to bioactivation antagonists for such receptor.


Subject(s)
Atherosclerosis/drug therapy , Drug Discovery/methods , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Animals , Atherosclerosis/metabolism , Humans , Receptors, Aryl Hydrocarbon/chemistry , Receptors, Aryl Hydrocarbon/metabolism
13.
Eur J Pharmacol ; 764: 173-188, 2015 Oct 05.
Article in English | MEDLINE | ID: mdl-26144375

ABSTRACT

AT1 antagonists effectively prevent atherosclerosis since AT1 upregulation and angiotensin II-induced proinflammatory actions are critical to atherogenesis. Despite the classic mechanisms underlying the vasoprotective and atheroprotective actions of AT1 antagonists, the cross-talk between angiotensin-converting enzyme-angiotensin II-AT1 and angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axes suggests other mechanisms beyond AT1 blockage in such effects. For instance, angiotensin-converting enzyme 2 activity is inhibited by reactive oxygen species derived from AT1-mediated proinflammatory signaling. Since angiotensin-(1-7) promotes antiatherogenic effects, we hypothesized that the vasoprotective and atheroprotective effects of AT1 antagonists could result from their inhibitory effects on the AT1-mediated negative modulation of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality. Interestingly, our results showed that early atherosclerosis triggered in thoracic aorta from high cholesterol fed-Apolipoprotein E-deficient mice impairs angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis functionality by a proinflammatory-redox AT1-mediated pathway. In such mechanism, AT1 activation leads to the aortic release of tumor necrosis factor-α, which stimulates NAD(P)H oxidase/Nox1-driven generation of superoxide and hydrogen peroxide. While hydrogen peroxide inhibits angiotensin-converting enzyme 2 activity, superoxide impairs MAS functionality. Candesartan treatment restored the functionality of angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis by inhibiting the proinflammatory-redox AT1-mediated mechanism. Candesartan also promoted vasoprotective and atheroprotective effects that were mediated by MAS since A779 (MAS antagonist) co-treatment inhibited them. The role of MAS receptors as the final mediators of the vasoprotective and atheroprotective effects of candesartan was supported by the vascular actions of angiotensin-(1-7) upon the recovery of the functionality of vascular angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS axis.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Angiotensin I/metabolism , Benzimidazoles/pharmacology , Cardiotonic Agents/pharmacology , Peptide Fragments/metabolism , Peptidyl-Dipeptidase A/metabolism , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , Tetrazoles/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Apolipoproteins E/genetics , Atherosclerosis/blood , Atherosclerosis/pathology , Biphenyl Compounds , Cholesterol/blood , Cytokines/genetics , Cytokines/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , NADH, NADPH Oxidoreductases/metabolism , NADPH Oxidase 1 , Proto-Oncogene Mas , Receptor, Angiotensin, Type 1/metabolism , Triglycerides/blood , Vascular Cell Adhesion Molecule-1/genetics
14.
Phytochemistry ; 71(11-12): 1423-9, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20541231

ABSTRACT

Diketopiperazine (DKP) derivatives, named colletopiperazine, fusaperazine C and E as well as four known DKPs were isolated from cultures of Colletotrichum gloeosporioides, Penicillium crustosum, both endophytic fungi isolated from Viguiera robusta, and a Fusarium spp., an endophyte of Viguiera arenaria, respectively. Their structures were established on the basis of their spectroscopic data. Conformational analysis of two known DKPs showed that folded conformations were as energetically stable as the extended one.


Subject(s)
Asteraceae/microbiology , Diketopiperazines/isolation & purification , Fungi/isolation & purification , Asteraceae/classification , Colletotrichum/chemistry , Diketopiperazines/chemistry , Fungi/chemistry , Fusarium/chemistry , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Penicillium/chemistry
15.
Eur J Med Chem ; 43(5): 996-1007, 2008 May.
Article in English | MEDLINE | ID: mdl-17804122

ABSTRACT

In this study, twenty hydroxylated and acetoxylated 3-phenylcoumarin derivatives were evaluated as inhibitors of immune complex-stimulated neutrophil oxidative metabolism and possible modulators of the inflammatory tissue damage found in type III hypersensitivity reactions. By using lucigenin- and luminol-enhanced chemiluminescence assays (CL-luc and CL-lum, respectively), we found that the 6,7-dihydroxylated and 6,7-diacetoxylated 3-phenylcoumarin derivatives were the most effective inhibitors. Different structural features of the other compounds determined CL-luc and/or CL-lum inhibition. The 2D-QSAR analysis suggested the importance of hydrophobic contributions to explain these effects. In addition, a statistically significant 3D-QSAR model built applying GRIND descriptors allowed us to propose a virtual receptor site considering pharmacophoric regions and mutual distances. Furthermore, the 3-phenylcoumarins studied were not toxic to neutrophils under the assessed conditions.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antigen-Antibody Complex/physiology , Coumarins/pharmacology , Neutrophils/drug effects , Quantitative Structure-Activity Relationship , Respiratory Burst , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Coumarins/chemistry , Female , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Luminescent Measurements , Models, Molecular , Neutrophils/metabolism , Rabbits , Reactive Oxygen Species/metabolism
16.
Toxicon ; 50(5): 724-30, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17669457

ABSTRACT

Monocrotaline is a pyrrolizidine alkaloid present in plants of the Crotalaria species, which causes cytotoxicity and genotoxicity, including hepatotoxicity in animals and humans. It is metabolized by cytochrome P-450 in the liver to the alkylating agent dehydromonocrotaline. We evaluated the effects of monocrotaline and its metabolite on respiration, membrane potential and ATP levels in isolated rat liver mitochondria, and on respiratory chain complex I NADH oxidase activity in submitochondrial particles. Dehydromonocrotaline, but not the parent compound, showed a concentration-dependent inhibition of glutamate/malate-supported state 3 respiration (respiratory chain complex I), but did not affect succinate-supported respiration (complex II). Only dehydromonocrotaline dissipated mitochondrial membrane potential, depleted ATP, and inhibited complex I NADH oxidase activity (IC50=62.06 microM) through a non-competitive type of inhibition (K(I)=8.1 microM). Therefore, dehydromonocrotaline is an inhibitor of the activity of respiratory chain complex I NADH oxidase, an action potentially accounting for the well-documented monocrotaline's hepatotoxicity to animals and humans. The mechanism probably involves change of the complex I conformation resulting from modification of cysteine thiol groups by the metabolite.


Subject(s)
Alkylating Agents/pharmacology , Chemical and Drug Induced Liver Injury/etiology , Electron Transport Complex I/drug effects , Enzyme Inhibitors/pharmacology , Mitochondria, Liver/drug effects , Monocrotaline/analogs & derivatives , Adenosine Triphosphate/metabolism , Animals , Chemical and Drug Induced Liver Injury/enzymology , Dose-Response Relationship, Drug , Electron Transport Complex I/antagonists & inhibitors , Male , Membrane Potential, Mitochondrial/drug effects , Mitochondria, Liver/enzymology , Monocrotaline/pharmacology , Multienzyme Complexes/metabolism , NADH, NADPH Oxidoreductases/metabolism , Oxygen Consumption/drug effects , Rats , Rats, Wistar , Submitochondrial Particles/drug effects , Submitochondrial Particles/enzymology
17.
J Biomol Struct Dyn ; 24(6): 515-24, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17508773

ABSTRACT

Alzheimer's disease (AD) affects approximately 10% of the world's population with 65 years of age, being the most common form of dementia in adults and is characterized by senile plaquets and cholinergic deficits. Many drugs currently used for the treatment of the AD are based on the improvement of cholinergic neurotransmission achieved by Acetylcholinesterase (AChE) inhibition, the enzyme responsible for acetylcholine hydrolysis. We have focused in this work on the usage of computer-aided molecular design by virtual screening, molecular dynamics with implicit and explicit water solvation, density functional, molecular interaction field studies, docking procedures, ADMET predictions in order to propose novel potential AChE inhibitor for the treatment of Alzheimer's disease.


Subject(s)
Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/therapeutic use , Calorimetry , Humans , Hydrogen Bonding , Models, Molecular , Molecular Conformation , User-Computer Interface
18.
Bioorg Med Chem ; 15(3): 1516-24, 2007 Feb 01.
Article in English | MEDLINE | ID: mdl-17112729

ABSTRACT

Twenty hydroxylated and acetoxylated 3-phenylcoumarins were synthesized, and the structure-activity relationships were investigated by evaluating the ability of these compounds to modulate horseradish peroxidase (HRP) catalytic activity and comparing the results to four flavonoids (quercetin, myricetin, kaempferol and galangin), previously reported as HRP inhibitors. It was observed that 3-phenylcoumarins bearing a catechol group were as active as quercetin and myricetin, which also show this substituent in the B-ring. The presence of 6,2'-dihydroxy group or 6,7,3',4'-tetraacetoxy group in the 3-phenylcoumarin structure also contributed to a significant inhibitory effect on the HRP activity. The catechol-containing 3-phenylcoumarin derivatives also showed free radical scavenger activity. Molecular modeling studies by docking suggested that interactions between the heme group in the HRP active site and the catechol group linked to the flavonoid B-ring or to the 3-phenyl coumarin ring are important to inhibit enzyme catalytic activity.


Subject(s)
Coumarins/chemical synthesis , Enzyme Inhibitors/pharmacology , Free Radical Scavengers/pharmacology , Horseradish Peroxidase/antagonists & inhibitors , Coumarins/chemistry , Coumarins/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Free Radical Scavengers/chemical synthesis , Free Radical Scavengers/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship
19.
J Mol Graph Model ; 25(2): 169-75, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16413803

ABSTRACT

Alzheimer's disease (AD) is the most common form of dementia in adults, which is characterized by senile plaquets and cholinergic deficit as the disease progresses. Improvement of cholinergic neurotransmission is the basis of some drugs currently used in the treatment of AD. It is achieved by acetylcholinesterase (AChE) inhibition, the enzyme responsible for acetylcholine hydrolysis. Molecular modeling techniques were of utmost importance to design a new pharmaceutical against Alzheimer's disease, with potential inhibitory activity over AChE, since the inhibition of human plasma butyrylcholinesterase (BChE) may cause side effects. Some of the drugs currently used in the treatment of AD are capable of increasing the cholinergic transmission through the AChE inhibition. In this work we proposed molecular hybrids of tacrine with donepezil (fusion of these structures), in order to suggest new proposals of AChE inhibitors for future treatment of AD. We have analyzed all the structures by docking, density functional studies and drug like properties.


Subject(s)
Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Cholinesterase Inhibitors/therapeutic use , Drug Design , Acetylcholinesterase/chemistry , Animals , Cholinesterase Inhibitors/chemistry , Donepezil , Humans , Indans/chemistry , Indans/therapeutic use , Models, Chemical , Models, Molecular , Molecular Structure , Piperidines/chemistry , Piperidines/therapeutic use , Protein Structure, Secondary , Tacrine/chemistry , Tacrine/therapeutic use
20.
Bioorg Chem ; 33(4): 274-84, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16023487

ABSTRACT

Molecular interaction field, density functional, and docking studies of novel potential ferrocene inhibitors of HIV-1 integrase (IN) are reported. The high docking scores, analysis of the ligand-receptor interactions in the active site as well as the molecular interaction potential calculations at the binding site of the receptor indicate important features for novel HIV-1 IN inhibitors. We also confirm in this work a novel binding trench in HIV-1 integrase, recently reported in a theoretical work by other authors. This observation may be interesting since the lack of detailed structural information about IN-ligand interactions has hampered the design of IN inhibitors. Our proposed ligands are open to experimental synthesis and testing.


Subject(s)
Drug Design , Ferrous Compounds/chemistry , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , Acids/chemistry , Binding Sites , HIV Integrase/chemistry , Hydrophobic and Hydrophilic Interactions , Ligands , Metallocenes , Models, Molecular , Protein Structure, Tertiary
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