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Papers by João Batista Júnior
Molecules, 2013
An antioxidant mechanism of tetrahydrocannabinol (THC) and cannabidiol (CBD) were compared with a... more An antioxidant mechanism of tetrahydrocannabinol (THC) and cannabidiol (CBD) were compared with a simplified model of α-tocopherol, butylhydroxytoluene and hydroxytoluene in order to understand the antioxidant nature of THC and CBD molecules using DFT. The following electronic properties were evaluated: frontier orbitals nature, ionization potential, O-H bond dissociation energy (BDE OH), stabilization energy, and spin density distribution. An important factor that shows an influence in the antioxidant property of THC is the electron abstraction at the phenol position. Our data indicate that the decrease of the HOMO values and the highest ionization potential values are related to phenol, ether, and alkyl moieties. On the other hand, BDE OH in molecules with the cyclohexenyl group at ortho position of phenol are formed from lower energies than the molecules with an ether group at the meta position. In the light of our results, the properties calculated here predict that THC has a sightly higher antioxidant potential than CBD.
Journal of Chemical and Pharmaceutical Research, 2014
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of autoimmune nature, it can... more Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of autoimmune nature, it can affects multiple organs and systems of unknown etiology, occurring more frequently in women of childbearing age and greater proportionality in relation to males. This study followed 57 patients suffering from SLE and assessed the possible therapeutic implications for use of glucocorticoids by these patients associated with depressive symptoms. From the data collected on the various drugs recommended for SLE patients' treatment, we found that about 80% of patients used at least one glucocorticoid. The results in our study demonstrate the relevance of depressive symptoms in SLE patients using glucocorticoids and thereby confirm that the pharmaceutical care, pharmacovigilance, and psychological care are of vital importance in conducting the safe and effective use of these drugs and in psychological support to these patients.
PLoS ONE, 2014
This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; ... more This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.51860.029 mg/mL) and paucibacillary (0.66260.123 mg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.
Virology: Current Research, 2020
The Coronaviridae family of viruses includes hundreds of viruses common in many different animal ... more The Coronaviridae family of viruses includes hundreds of viruses common in many different animal species and humans. Seven coronaviruses (CoVs) are known to cause disease in humans. Four of them show low pathogenicity and are endemic in humans and the other three CoV are particularly dangerous and highly pathogenic viruses, which underwent genetic changes rendering them able to jump the species barriers from animal host to humans and also to spread efficiently among humans. SARS-CoV-2 is the seventh coronavirus known to infect humans. The S protein mediates attachment and viral and host cell membrane fusion. The receptor-binding domains (RBDs) are regions in S protein responsible for receptor recognition. Human angiotensin-converting enzyme 2 (ACE2) is recognized by HCoV-NL63, SARS-CoV and SARS-CoV-2 as their functional receptor.
Interaction energy analysis were performed to unveil how precisely SARS-CoV-2 interacts with ACE2 by identifying which amino acid residues are responsible for the interactions across S protein-ACE2 interfaces and how they contribute to the strength, stability and specificity of S protein interactions.
Interaction energies acting on molecular recognition of ACE2 by HCoV-NL63, SARS-CoV and SARS-CoV-2 conduced to a naturally evolved RBD with different combinations of amino acids, providing SARS-CoV-2 binding interface more interacting residue pairs, more hydrogen bonds, increased number of residues engaged in hydrogen bonding, allowing for better distribution of hydrogen bond per residue in interface than SARS-CoV or HCoV-NL63, includes salt bridge, and adds new van der Waals contacts into the network.
Residues across the SARS-CoV and SARS-CoV -2 homologous sequences have been chosen to be remarkably evolutionary conserved in the regions mediating binding of these viruses because of their dominant hydrogen bonding contribution to binding stability to ACE2. SARS-CoV-2 achieves higher binding affinity than SARS-CoV and HCoV-NL63 to human ACE2 molecular recognition primarily by combining its richer interaction network and higher binding stability.
This study presents a comprehensive and quantitative analysis of interaction energies of the human ACE2 molecular recognition by CoVs that may contribute to further understand the higher infectivity and transmissibility of SARS-CoV-2 compared to SARS-CoV and HCoV-NL63, furthermore, this could help explain why SARS-CoV-2 has an enhanced ability for pathogenicity.
Memórias do Instituto Oswaldo Cruz, 2010
This study is the first report on genetic differences between isolates of Paracoccidioides brasil... more This study is the first report on genetic differences between isolates of Paracoccidioides brasiliensis from a single patient. We describe a simultaneous infection with genetically distinct isolates of P. brasiliensis in a patient with chronic paracoccidioidomycosis. The clinical isolates were obtained from lesions in different anatomical sites and were characterised by random amplified polymorphic DNA (RAPD) analysis. The RAPD technique can be helpful for distinguishing between clinical isolates. Different random primers were used to characterise these clinical isolates. The RAPD patterns allowed for differentiation between isolates and the construction of a phenetic tree, which showed more than 28% genetic variability in this fungal species, opening new possibilities for clinical studies of P. brasiliensis. Based on these results and preliminary clinical findings, we suggest that different genotypes of P. brasiliensis might infect the same patient, inducing the active form of the disease.
Infarma - Ciências Farmacêuticas, Jan 28, 2013
A aprendizagem baseada em projeto é uma metodologia dinâmica de ensino na qual os estudantes expl... more A aprendizagem baseada em projeto é uma metodologia dinâmica de ensino na qual os estudantes exploram problemas e desafios do mundo real e, simultaneamente, desenvolvem habilidades interdisciplinares enquanto trabalham em pequenos grupos colaborativos. Os fármacos anti-inflamatórios são os mais comercializados, em todo o mundo, porém com seu uso inadequado apresentam muitos efeitos colaterais dentre eles os distúrbios gastrintestinais. Melhoras vêm sendo buscadas na elaboração de novos fármacos com menos efeitos colaterais. A Química Farmacêutica e Medicinal moderna, através do auxílio de suas ferramentas computacionais, nos possibilita diminuir muitos passos no desenvolvimento de novos fármacos. Portanto, este trabalho foi desenvolvido com base na metodologia de Aprendizagem Baseada em Projeto aplicando-se os recursos de ferramentas computacionais disponíveis visando desenvolver um novo fármaco antiinflamatório derivado análogo do diclofenaco cujas propriedades bioativas sejam a inibição seletiva da ciclooxigenase-2 (COX-2).
Drafts by João Batista Júnior
ChemRxiv, 2020
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a novel coronavirus i... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a novel coronavirus in late 2019, since then it is infecting people and spreading efficiently among humans worldwide, causing the infectious disease named coronavirus disease 2019 (COVID-19). Some patients infected with SARS-CoV-2 develop severe inflammatory‐induced lung injury as a result of a cytokine storm syndrome (CSS), which may cause acute respiratory distress syndrome (ARDS), the main cause of mortality in SARS-CoV-2 patients. Tumor necrosis factor alpha converting enzyme (TACE) controls by ectodomain shedding the bioavailability and release of various cell surface bound signaling molecules, many of them are inflammation mediators, as the cytokine TNFα, one of the molecules most affected by TACE.
In severely or critically ill patients, the host immune response to the SARS-CoV-2 infection is hyperactive, resulting in an excessive inflammatory response, forcing TACE to hyperexcitability proteolytic activity state. This TACE over-induction state results in aberrant ectodomain shedding of multitude of TACE membrane-bound substrates, releasing massive amount of cytokine TNF-α and other inflammation mediators, that may trigger more inflammation in those patients leading to CSS, cellular dysfunction, cell death, and tissue damage and ARDS. Over-induction of TACE activity may be attenuated by temporarily targeting TACE with specific inhibitors that significantly decrease tissue and plasma levels of circulating proinflammatory cytokines.
This research corresponds to virtual screening of FDA-approved drug library and molecular modeling analysis of selected drugs in the experimental crystal structure of TACE. This study reveals that rosiglitazone and pioglitazone, two already approved therapeutic agents to treat type II diabetes, were found to bind favorably to TACE catalytic site with highlighted binding features. These results suggest rosiglitazone and pioglitazone thus might open a new potential therapeutic approach toward the drug repurposing of these thiazolidinediones for temporally and specifically inhibit TACE to treat SARS-CoV-2 infection-associated aberrant systemic inflammatory response and, consequently, to diminish tissue damage and death rates associated with CSS and ARDS among SARS-CoV-2 patients. This study provides scientific information for the selection of rosiglitazone and pioglitazone to be further validated in vivo.
Molecules, 2013
An antioxidant mechanism of tetrahydrocannabinol (THC) and cannabidiol (CBD) were compared with a... more An antioxidant mechanism of tetrahydrocannabinol (THC) and cannabidiol (CBD) were compared with a simplified model of α-tocopherol, butylhydroxytoluene and hydroxytoluene in order to understand the antioxidant nature of THC and CBD molecules using DFT. The following electronic properties were evaluated: frontier orbitals nature, ionization potential, O-H bond dissociation energy (BDE OH), stabilization energy, and spin density distribution. An important factor that shows an influence in the antioxidant property of THC is the electron abstraction at the phenol position. Our data indicate that the decrease of the HOMO values and the highest ionization potential values are related to phenol, ether, and alkyl moieties. On the other hand, BDE OH in molecules with the cyclohexenyl group at ortho position of phenol are formed from lower energies than the molecules with an ether group at the meta position. In the light of our results, the properties calculated here predict that THC has a sightly higher antioxidant potential than CBD.
Journal of Chemical and Pharmaceutical Research, 2014
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of autoimmune nature, it can... more Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of autoimmune nature, it can affects multiple organs and systems of unknown etiology, occurring more frequently in women of childbearing age and greater proportionality in relation to males. This study followed 57 patients suffering from SLE and assessed the possible therapeutic implications for use of glucocorticoids by these patients associated with depressive symptoms. From the data collected on the various drugs recommended for SLE patients' treatment, we found that about 80% of patients used at least one glucocorticoid. The results in our study demonstrate the relevance of depressive symptoms in SLE patients using glucocorticoids and thereby confirm that the pharmaceutical care, pharmacovigilance, and psychological care are of vital importance in conducting the safe and effective use of these drugs and in psychological support to these patients.
PLoS ONE, 2014
This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; ... more This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.51860.029 mg/mL) and paucibacillary (0.66260.123 mg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.
Virology: Current Research, 2020
The Coronaviridae family of viruses includes hundreds of viruses common in many different animal ... more The Coronaviridae family of viruses includes hundreds of viruses common in many different animal species and humans. Seven coronaviruses (CoVs) are known to cause disease in humans. Four of them show low pathogenicity and are endemic in humans and the other three CoV are particularly dangerous and highly pathogenic viruses, which underwent genetic changes rendering them able to jump the species barriers from animal host to humans and also to spread efficiently among humans. SARS-CoV-2 is the seventh coronavirus known to infect humans. The S protein mediates attachment and viral and host cell membrane fusion. The receptor-binding domains (RBDs) are regions in S protein responsible for receptor recognition. Human angiotensin-converting enzyme 2 (ACE2) is recognized by HCoV-NL63, SARS-CoV and SARS-CoV-2 as their functional receptor.
Interaction energy analysis were performed to unveil how precisely SARS-CoV-2 interacts with ACE2 by identifying which amino acid residues are responsible for the interactions across S protein-ACE2 interfaces and how they contribute to the strength, stability and specificity of S protein interactions.
Interaction energies acting on molecular recognition of ACE2 by HCoV-NL63, SARS-CoV and SARS-CoV-2 conduced to a naturally evolved RBD with different combinations of amino acids, providing SARS-CoV-2 binding interface more interacting residue pairs, more hydrogen bonds, increased number of residues engaged in hydrogen bonding, allowing for better distribution of hydrogen bond per residue in interface than SARS-CoV or HCoV-NL63, includes salt bridge, and adds new van der Waals contacts into the network.
Residues across the SARS-CoV and SARS-CoV -2 homologous sequences have been chosen to be remarkably evolutionary conserved in the regions mediating binding of these viruses because of their dominant hydrogen bonding contribution to binding stability to ACE2. SARS-CoV-2 achieves higher binding affinity than SARS-CoV and HCoV-NL63 to human ACE2 molecular recognition primarily by combining its richer interaction network and higher binding stability.
This study presents a comprehensive and quantitative analysis of interaction energies of the human ACE2 molecular recognition by CoVs that may contribute to further understand the higher infectivity and transmissibility of SARS-CoV-2 compared to SARS-CoV and HCoV-NL63, furthermore, this could help explain why SARS-CoV-2 has an enhanced ability for pathogenicity.
Memórias do Instituto Oswaldo Cruz, 2010
This study is the first report on genetic differences between isolates of Paracoccidioides brasil... more This study is the first report on genetic differences between isolates of Paracoccidioides brasiliensis from a single patient. We describe a simultaneous infection with genetically distinct isolates of P. brasiliensis in a patient with chronic paracoccidioidomycosis. The clinical isolates were obtained from lesions in different anatomical sites and were characterised by random amplified polymorphic DNA (RAPD) analysis. The RAPD technique can be helpful for distinguishing between clinical isolates. Different random primers were used to characterise these clinical isolates. The RAPD patterns allowed for differentiation between isolates and the construction of a phenetic tree, which showed more than 28% genetic variability in this fungal species, opening new possibilities for clinical studies of P. brasiliensis. Based on these results and preliminary clinical findings, we suggest that different genotypes of P. brasiliensis might infect the same patient, inducing the active form of the disease.
Infarma - Ciências Farmacêuticas, Jan 28, 2013
A aprendizagem baseada em projeto é uma metodologia dinâmica de ensino na qual os estudantes expl... more A aprendizagem baseada em projeto é uma metodologia dinâmica de ensino na qual os estudantes exploram problemas e desafios do mundo real e, simultaneamente, desenvolvem habilidades interdisciplinares enquanto trabalham em pequenos grupos colaborativos. Os fármacos anti-inflamatórios são os mais comercializados, em todo o mundo, porém com seu uso inadequado apresentam muitos efeitos colaterais dentre eles os distúrbios gastrintestinais. Melhoras vêm sendo buscadas na elaboração de novos fármacos com menos efeitos colaterais. A Química Farmacêutica e Medicinal moderna, através do auxílio de suas ferramentas computacionais, nos possibilita diminuir muitos passos no desenvolvimento de novos fármacos. Portanto, este trabalho foi desenvolvido com base na metodologia de Aprendizagem Baseada em Projeto aplicando-se os recursos de ferramentas computacionais disponíveis visando desenvolver um novo fármaco antiinflamatório derivado análogo do diclofenaco cujas propriedades bioativas sejam a inibição seletiva da ciclooxigenase-2 (COX-2).
ChemRxiv, 2020
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a novel coronavirus i... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a novel coronavirus in late 2019, since then it is infecting people and spreading efficiently among humans worldwide, causing the infectious disease named coronavirus disease 2019 (COVID-19). Some patients infected with SARS-CoV-2 develop severe inflammatory‐induced lung injury as a result of a cytokine storm syndrome (CSS), which may cause acute respiratory distress syndrome (ARDS), the main cause of mortality in SARS-CoV-2 patients. Tumor necrosis factor alpha converting enzyme (TACE) controls by ectodomain shedding the bioavailability and release of various cell surface bound signaling molecules, many of them are inflammation mediators, as the cytokine TNFα, one of the molecules most affected by TACE.
In severely or critically ill patients, the host immune response to the SARS-CoV-2 infection is hyperactive, resulting in an excessive inflammatory response, forcing TACE to hyperexcitability proteolytic activity state. This TACE over-induction state results in aberrant ectodomain shedding of multitude of TACE membrane-bound substrates, releasing massive amount of cytokine TNF-α and other inflammation mediators, that may trigger more inflammation in those patients leading to CSS, cellular dysfunction, cell death, and tissue damage and ARDS. Over-induction of TACE activity may be attenuated by temporarily targeting TACE with specific inhibitors that significantly decrease tissue and plasma levels of circulating proinflammatory cytokines.
This research corresponds to virtual screening of FDA-approved drug library and molecular modeling analysis of selected drugs in the experimental crystal structure of TACE. This study reveals that rosiglitazone and pioglitazone, two already approved therapeutic agents to treat type II diabetes, were found to bind favorably to TACE catalytic site with highlighted binding features. These results suggest rosiglitazone and pioglitazone thus might open a new potential therapeutic approach toward the drug repurposing of these thiazolidinediones for temporally and specifically inhibit TACE to treat SARS-CoV-2 infection-associated aberrant systemic inflammatory response and, consequently, to diminish tissue damage and death rates associated with CSS and ARDS among SARS-CoV-2 patients. This study provides scientific information for the selection of rosiglitazone and pioglitazone to be further validated in vivo.