Magaly G Albuquerque | Universidade Federal do Rio de Janeiro (UFRJ) (original) (raw)
Papers by Magaly G Albuquerque
The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by... more The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by the human genome. These receptors are membrane proteins which share a common structure of seven transmembrane helices and are involved in the cellular signal transduction through activation of heterotrimeric protein (G protein) in intracellular environment. This activation signal, mediated by the agonist binding to the extracellular domain of the receptor, is transmitted into the cell and activates many signaling cascades in different physiological events such as neurotransmission, growth, metabolism, differentiation of the cell, secretion and immune defense. As a consequence, these receptors are described as therapeutic targets for more than 50% of drugs sold worldwide. Thus, the study of the molecular mechanism involving GPCRs has become essential to understand the cellular signaling and, consequently, the rational design of new therapeutic agents, e.g. antihypertensive drugs. Therefore, this review reports the structural characteristics, the activation mechanism, the G protein activation and the classification of these membrane proteins of huge physiological and pathophysiological importance.
Revista Virtual de Química, 2013
The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by... more The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by the human genome. These receptors are membrane proteins which share a common structure of seven transmembrane helices and are involved in the cellular signal transduction through activation of heterotrimeric protein (G protein) in intracellular environment. This activation signal, mediated by the agonist binding to the extracellular domain of the receptor, is transmitted into the cell and activates many signaling cascades in different physiological events such as neurotransmission, growth, metabolism, differentiation of the cell, secretion and immune defense. As a consequence, these receptors are described as therapeutic targets for more than 50% of drugs sold worldwide. Thus, the study of the molecular mechanism involving GPCRs has become essential to understand the cellular signaling and, consequently, the rational design of new therapeutic agents, e.g. antihypertensive drugs. Therefore, this review reports the structural characteristics, the activation mechanism, the G protein activation and the classification of these membrane proteins of huge physiological and pathophysiological importance.
Revista Virtual de Química, 2014
The acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV)... more The acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV) that infects cells of the immune system, destroying them or causing damage to its operation. Among all the HIV enzymes, integrase is responsible for the insertion of viral DNA in the host DNA. The aim of this article is to describe the integrase inhibitors drugs and report cases of resistance, in addition to discussing new promising compounds that are being evaluated as integrase inhibitors. Currently, there are only three drugs in clinical use that belong to the class of integrase inhibitors: raltegravir (a pirimidinone carboxamide derivative, elvitegravir (a quinoline derivative) and dolutegravir (a diazatricyclo carboxamide derivative). However, several cases of resistance to drugs of this class are described in the literature, and the mutations of the enzyme responsible for such profile are known. Many compounds with integrase inhibitory action are under development. The use of the integrase enzyme as a target against HIV/AIDS infection is promising. In addition, the integration is a complex stage of the viral replication cycle, and new details of this process are being discovered every minute, which encourages the accomplishment of more studies for the development of new drugs of this class.
Journal of chemical and pharmaceutical research, 2010
In the present work, we carried out a quantitative structure-activity relationship (QSAR) study, ... more In the present work, we carried out a quantitative structure-activity relationship (QSAR) study, using 15 phenolic compounds with antioxidant activi ty. For each compound, two electronic properties, BDE-OH (OH bond homolytic dissociation e thalpy) and IP (ionization potential), and two lipophylic parameters, LogP (lipophilicity) and LogD (relative lipophilicity), were estimated. The best QSAR model obtained by multiple regr ssion analysis, using the systematic approach for variable selection, corresponds to the equation: pIC50 = 6.68 – 0.023(BDE-OH) – 0.0036(IP), which showed a high statistical signifi cance (N = 15, R = 0.941, R 2 = 0.885, Q = 0.807, s = 0.057, F = 46.09, p = 0.05).
Platelets plays a central role in hemostatic processes and consequently are similarly involved in... more Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N '-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). Methods: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPAR-TAN' 08 program, in silico ADMET screening and the Lipinski "rule of five" using Osiris Property Explorer and molinspiration on-line programs. Results: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c-IC50 61 M and 68 M respectively) almost 5-fold more potent than aspirin (IC50 300 M). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. Conclusion: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.
European Journal of Medicinal Chemistry
Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 12, 2018
Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most impor... more Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy,and the development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry. Synthesis and antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing the 1,2,3-1H triazole isatin scaffold. The 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for i...
Pharmaceuticals (Basel, Switzerland), Jan 9, 2017
In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized... more In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (...
Int J Quantum Chem, 1995
ELIEZER J. BARREIRO Laborat6rio de Avalia@o e Sintese de Substlincias Bioativas (LASSBio), CP 680... more ELIEZER J. BARREIRO Laborat6rio de Avalia@o e Sintese de Substlincias Bioativas (LASSBio), CP 68006, Depto. Tecnologia Farmace^utica, Faculdade de Farmicia, UFRJ, CEP 21944-910, Brasil ... Leukotrienes and thromboxane A , are autacoids derived from ...
Bioorganic Medicinal Chemistry, 2008
Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we ... more Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a-i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure-activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2016
Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently,... more Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N 0-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE 2 and TXB 2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.
Revista Virtual De Quimica, Apr 10, 2013
European Journal of Medicinal Chemistry, Mar 31, 2002
In this work, we have developed a new descriptor, named local intersection volume (LIV), in order... more In this work, we have developed a new descriptor, named local intersection volume (LIV), in order to compose a 3D-QSAR pharmacophore model for benzodiazepine receptor ligands. The LIV can be classified as a 3D local shape descriptor in contraposition to the global shape descriptors. We have selected from the literature 49 non-benzodiazepine compounds as a training data set and the model was obtained and evaluated by genetic algorithms (GA) and partial least-squares (PLS) methods using LIVs as descriptors. The LIV 3D-QSAR model has a good predictive capacity according the cross-validation test by "leave-one-out" procedure (Q(2)=0.72). The developed model was compared to a comprehensive and extensive SAR pharmacophore model, recently proposed by Cook and co-workers, for benzodiazepine receptor ligands [J. Med. Chem. 43 (2000) 71]. It showed a relevant correlation with the pharmacophore groups pointed out in that work. Our LIV 3D-QSAR model was also able to predict affinity values for a series of nine compounds (test data set) that was not included into the training data set.
Chemical Biology & Drug Design
Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) stu... more Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q(2) above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases...
Journal of Molecular Modeling
Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revea... more Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole-indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode betwee...
Materials and Corrosion, 2008
This work aims to analyze, through weight loss and X-ray photoelectron spectroscopy (XPS) methods... more This work aims to analyze, through weight loss and X-ray photoelectron spectroscopy (XPS) methods, the inhibitive films of 1-hydroxyethane-1,1-diphosphonic acid (1-hydroxyethylidene-1,1-diphosphonic acid, HEDP) and zinc(II) ions formed on AISI 1020 carbon steel when immersed in solutions containing 30 ppm of chloride ions, 50 ppm of HEDP, and three different concentrations of zinc(II) ions (14, 20, and 30 ppm). Moreover, the results of the experimental surface analyses were compared to molecular modeling studies of the proposed HEDP-Fe(III)/Zn(OH) 2 /HEDP-Zn(II) protective film. The film presented dissimilar structures responsible for the different levels of metallic protection for each particular zinc(II) concentration. In general, the increase in Zn(II) concentration leads to more compact and adherent film formation, with decreased corrosion rates of carbon steel.
Journal of Molecular Structure, 2011
Eight human herpes viruses (e.g., herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus... more Eight human herpes viruses (e.g., herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus, Kaposi’s sarcoma) are responsible for several diseases from sub-clinic manifestations to fatal infections, mostly in immunocompromised patients. The major limitations of the currently available antiviral drug therapy are drug resistance, host toxicity, and narrow spectrum of activity. However, some non-nucleoside 1,4-dihydro-4-oxoquinoline derivatives (e.g., PNU-183792) [4] shows broad spectrum antiviral activity. We have developed molecular modeling studies, including molecular docking and molecular dynamics simulations, based on a model proposed by Liu and co-workers [14] in order to understand the mechanism of action of a 6-chloro substituted 1,4-dihydro-4-oxoquinoline ribonucleoside, synthesized by the synthetic group, which showed anti-HSV-1 activity [9]. The molecular docking simulations confirmed the Liu’s model showing that the ligand needs to dislocate template residues from the active site in order to interact with the viral DNA polymerase enzyme, reinforcing that the interaction with the Val823 residue is pivotal for the inhibitory activity of non-nucleoside 1,4-dihydro-4-oxoquinoline derivatives, such as PNU-183792, with the HSV-1. The molecular dynamics simulations showed that the 6-chloro-benzyl group of PNU-183792 maintains its interaction with residues of the HSV-1 DNA polymerase hydrophobic pocket, considered important according to the Liu’s model, and also showed that the methyl group bounded to the nitrogen atom from PNU-183792 is probably contributing to a push–pull effect with the carbonyl group.
The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by... more The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by the human genome. These receptors are membrane proteins which share a common structure of seven transmembrane helices and are involved in the cellular signal transduction through activation of heterotrimeric protein (G protein) in intracellular environment. This activation signal, mediated by the agonist binding to the extracellular domain of the receptor, is transmitted into the cell and activates many signaling cascades in different physiological events such as neurotransmission, growth, metabolism, differentiation of the cell, secretion and immune defense. As a consequence, these receptors are described as therapeutic targets for more than 50% of drugs sold worldwide. Thus, the study of the molecular mechanism involving GPCRs has become essential to understand the cellular signaling and, consequently, the rational design of new therapeutic agents, e.g. antihypertensive drugs. Therefore, this review reports the structural characteristics, the activation mechanism, the G protein activation and the classification of these membrane proteins of huge physiological and pathophysiological importance.
Revista Virtual de Química, 2013
The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by... more The G protein-coupled receptors (GPCRs) constitute the largest superfamily of proteins encoded by the human genome. These receptors are membrane proteins which share a common structure of seven transmembrane helices and are involved in the cellular signal transduction through activation of heterotrimeric protein (G protein) in intracellular environment. This activation signal, mediated by the agonist binding to the extracellular domain of the receptor, is transmitted into the cell and activates many signaling cascades in different physiological events such as neurotransmission, growth, metabolism, differentiation of the cell, secretion and immune defense. As a consequence, these receptors are described as therapeutic targets for more than 50% of drugs sold worldwide. Thus, the study of the molecular mechanism involving GPCRs has become essential to understand the cellular signaling and, consequently, the rational design of new therapeutic agents, e.g. antihypertensive drugs. Therefore, this review reports the structural characteristics, the activation mechanism, the G protein activation and the classification of these membrane proteins of huge physiological and pathophysiological importance.
Revista Virtual de Química, 2014
The acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV)... more The acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV) that infects cells of the immune system, destroying them or causing damage to its operation. Among all the HIV enzymes, integrase is responsible for the insertion of viral DNA in the host DNA. The aim of this article is to describe the integrase inhibitors drugs and report cases of resistance, in addition to discussing new promising compounds that are being evaluated as integrase inhibitors. Currently, there are only three drugs in clinical use that belong to the class of integrase inhibitors: raltegravir (a pirimidinone carboxamide derivative, elvitegravir (a quinoline derivative) and dolutegravir (a diazatricyclo carboxamide derivative). However, several cases of resistance to drugs of this class are described in the literature, and the mutations of the enzyme responsible for such profile are known. Many compounds with integrase inhibitory action are under development. The use of the integrase enzyme as a target against HIV/AIDS infection is promising. In addition, the integration is a complex stage of the viral replication cycle, and new details of this process are being discovered every minute, which encourages the accomplishment of more studies for the development of new drugs of this class.
Journal of chemical and pharmaceutical research, 2010
In the present work, we carried out a quantitative structure-activity relationship (QSAR) study, ... more In the present work, we carried out a quantitative structure-activity relationship (QSAR) study, using 15 phenolic compounds with antioxidant activi ty. For each compound, two electronic properties, BDE-OH (OH bond homolytic dissociation e thalpy) and IP (ionization potential), and two lipophylic parameters, LogP (lipophilicity) and LogD (relative lipophilicity), were estimated. The best QSAR model obtained by multiple regr ssion analysis, using the systematic approach for variable selection, corresponds to the equation: pIC50 = 6.68 – 0.023(BDE-OH) – 0.0036(IP), which showed a high statistical signifi cance (N = 15, R = 0.941, R 2 = 0.885, Q = 0.807, s = 0.057, F = 46.09, p = 0.05).
Platelets plays a central role in hemostatic processes and consequently are similarly involved in... more Platelets plays a central role in hemostatic processes and consequently are similarly involved in pathological processes, such as arterial thrombosis and atherosclerosis. Herein we described the synthesis, antiplatelet profile and structure-activity relationship (SAR) of a new series of N '-substitutedphenylmethylene-1H-pyrazolo[3,4-b]pyridine-carbohydrazide derivatives (3a-3k). Methods: These compounds were synthesized in good yield and tested in platelet aggregation assays using collagen, ADP and arachidonic acid as agonists. We also performed a SAR studies using SPAR-TAN' 08 program, in silico ADMET screening and the Lipinski "rule of five" using Osiris Property Explorer and molinspiration on-line programs. Results: Interestingly, the new compounds were active against collagen and arachidonic acid (AA) with the two most actives compounds (3a and 3c-IC50 61 M and 68 M respectively) almost 5-fold more potent than aspirin (IC50 300 M). These derivatives showed low theoretical toxicity risks in in silico ADMET screening and fulfilled the Lipinski rule of five, suggesting good oral biodisponibility. Conclusion: This work showed carbohydrazide group as potential for designing new antiplatelets. On that purpose, 3a and 3c may act as prototypes to generate more efficient and safe molecules for treating thrombotic diseases.
European Journal of Medicinal Chemistry
Medicinal chemistry (Shariqah (United Arab Emirates)), Jan 12, 2018
Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most impor... more Chagas disease, also known as American trypanosomiasis, is classified as one of the 17 most important neglected diseases by the World Health Organization. The only drugs with proven efficacy against Chagas disease are benznidazole and nifurtimox, however both show adverse effects, poor clinical efficacy,and the development of resistance. For these reasons, the search for new effective chemical entities is a challenge to research groups and the pharmaceutical industry. Synthesis and antitrypanosomal activities of a series of thiosemicarbazones and semicarbazones containing the 1,2,3-1H triazole isatin scaffold. The 5'-(4-alkyl/aryl)-1H-1,2,3-triazole-isatins were prepared by Huisgen 1,3-dipolar cycloaddition and the thiosemicarbazones and semicarbazones were obtained by the 1:1 reactions of the carbonylated derivatives with thiosemicarbazide and semicarbazide hydrochloride, respectively, in methanol, using conventional reflux or microwave heating. The compounds were assayed for i...
Pharmaceuticals (Basel, Switzerland), Jan 9, 2017
In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized... more In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (...
Int J Quantum Chem, 1995
ELIEZER J. BARREIRO Laborat6rio de Avalia@o e Sintese de Substlincias Bioativas (LASSBio), CP 680... more ELIEZER J. BARREIRO Laborat6rio de Avalia@o e Sintese de Substlincias Bioativas (LASSBio), CP 68006, Depto. Tecnologia Farmace^utica, Faculdade de Farmicia, UFRJ, CEP 21944-910, Brasil ... Leukotrienes and thromboxane A , are autacoids derived from ...
Bioorganic Medicinal Chemistry, 2008
Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we ... more Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a-j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a-i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure-activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2016
Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently,... more Platelet aggregation is one of the main events involved in vascular thrombus formation. Recently, N 0-substituted-phenylmethylene-3-methyl-1,6-diphenyl-1H-pyrazolo[3,4-b]pyridine-4carbohydrazides were described as antiplatelet derivatives. In this work, we explore the properties of these antiplatelet agents through a series of pharmacological, biochemical and toxicological studies. The antiplatelet activity of each derivative was confirmed as 3a, 3b and 3 h significantly inhibited human platelet aggregation induced by arachidonic acid, with no detectable effect on clotting factors or healthy erythrocytes. Importantly, mice treated with derivative 3a showed a higher survival rate at an in vivo model of pulmonary thromboembolism with a lower bleeding risk in comparison to aspirin. The in silico studies pointed a series of structural parameters related to thromboxane synthase (TXS) inhibition by 3a, which was confirmed by tracking plasma levels of PGE 2 and TXB 2 through an in vitro enzyme immunoassay. Derivative 3a showed selective TXS inhibition allied with low bleeding risk and increased animal survival, revealing the derivative as a promising candidate for treatment of cardiovascular diseases.
Revista Virtual De Quimica, Apr 10, 2013
European Journal of Medicinal Chemistry, Mar 31, 2002
In this work, we have developed a new descriptor, named local intersection volume (LIV), in order... more In this work, we have developed a new descriptor, named local intersection volume (LIV), in order to compose a 3D-QSAR pharmacophore model for benzodiazepine receptor ligands. The LIV can be classified as a 3D local shape descriptor in contraposition to the global shape descriptors. We have selected from the literature 49 non-benzodiazepine compounds as a training data set and the model was obtained and evaluated by genetic algorithms (GA) and partial least-squares (PLS) methods using LIVs as descriptors. The LIV 3D-QSAR model has a good predictive capacity according the cross-validation test by "leave-one-out" procedure (Q(2)=0.72). The developed model was compared to a comprehensive and extensive SAR pharmacophore model, recently proposed by Cook and co-workers, for benzodiazepine receptor ligands [J. Med. Chem. 43 (2000) 71]. It showed a relevant correlation with the pharmacophore groups pointed out in that work. Our LIV 3D-QSAR model was also able to predict affinity values for a series of nine compounds (test data set) that was not included into the training data set.
Chemical Biology & Drug Design
Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) stu... more Receptor-dependent four-dimensional quantitative structure-activity relationship (RD-4D-QSAR) studies were applied on a series of 21 peptides reversible inhibitors of Trypanosoma cruzi trypanothione reductase (TR) (Amino Acids, 20, 2001, 145). The RD-4D-QSAR (J Chem Inform Comp Sci, 43, 2003, 1591) approach can evaluate multiple conformations from molecular dynamics simulation and several superposition structure alignments inside a box composed by unitary cubic cells. The descriptors are the occupancy frequency of the atoms types inside the grid cells. We could develop 3D-QSAR models that were highly predictive (q(2) above 0.71). The 3D-QSAR models can be visualized as a spatial map of atom types that are important on the comprehension of the ligand-enzyme interaction mechanism, pointing main pharmacophoric groups and TR subsites described in the literature. We were able also to identify some TR subsites for further development in the drug discovery process against tropical diseases...
Journal of Molecular Modeling
Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revea... more Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole-indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode betwee...
Materials and Corrosion, 2008
This work aims to analyze, through weight loss and X-ray photoelectron spectroscopy (XPS) methods... more This work aims to analyze, through weight loss and X-ray photoelectron spectroscopy (XPS) methods, the inhibitive films of 1-hydroxyethane-1,1-diphosphonic acid (1-hydroxyethylidene-1,1-diphosphonic acid, HEDP) and zinc(II) ions formed on AISI 1020 carbon steel when immersed in solutions containing 30 ppm of chloride ions, 50 ppm of HEDP, and three different concentrations of zinc(II) ions (14, 20, and 30 ppm). Moreover, the results of the experimental surface analyses were compared to molecular modeling studies of the proposed HEDP-Fe(III)/Zn(OH) 2 /HEDP-Zn(II) protective film. The film presented dissimilar structures responsible for the different levels of metallic protection for each particular zinc(II) concentration. In general, the increase in Zn(II) concentration leads to more compact and adherent film formation, with decreased corrosion rates of carbon steel.
Journal of Molecular Structure, 2011
Eight human herpes viruses (e.g., herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus... more Eight human herpes viruses (e.g., herpes simplex, varicella-zoster, Epstein-Barr, cytomegalovirus, Kaposi’s sarcoma) are responsible for several diseases from sub-clinic manifestations to fatal infections, mostly in immunocompromised patients. The major limitations of the currently available antiviral drug therapy are drug resistance, host toxicity, and narrow spectrum of activity. However, some non-nucleoside 1,4-dihydro-4-oxoquinoline derivatives (e.g., PNU-183792) [4] shows broad spectrum antiviral activity. We have developed molecular modeling studies, including molecular docking and molecular dynamics simulations, based on a model proposed by Liu and co-workers [14] in order to understand the mechanism of action of a 6-chloro substituted 1,4-dihydro-4-oxoquinoline ribonucleoside, synthesized by the synthetic group, which showed anti-HSV-1 activity [9]. The molecular docking simulations confirmed the Liu’s model showing that the ligand needs to dislocate template residues from the active site in order to interact with the viral DNA polymerase enzyme, reinforcing that the interaction with the Val823 residue is pivotal for the inhibitory activity of non-nucleoside 1,4-dihydro-4-oxoquinoline derivatives, such as PNU-183792, with the HSV-1. The molecular dynamics simulations showed that the 6-chloro-benzyl group of PNU-183792 maintains its interaction with residues of the HSV-1 DNA polymerase hydrophobic pocket, considered important according to the Liu’s model, and also showed that the methyl group bounded to the nitrogen atom from PNU-183792 is probably contributing to a push–pull effect with the carbonyl group.