Glaucio Monteiro Ferreira - Academia.edu (original) (raw)

Papers by Glaucio Monteiro Ferreira

ChemMedChem, Feb 14, 2023

Letters in Drug Design & Discovery

Background: Glioblastoma is one of the most aggressive types of tumors, which occurs in the centr... more Background: Glioblastoma is one of the most aggressive types of tumors, which occurs in the central nervous system, and has a high fatality rate. Among the cellular changes observed in glioblastoma is the overexpression of certain anti-apoptotic proteins, such as Bcl-xL. Recently, the alkaloid sanguinarine (SAN) was identified as a potent inhibitor of this class of proteins. Objective: In this work, the antitumor activity of ten aryl-isoquinolines that were synthesized based on molecular simplification of SAN was investigated. Methods: The SAN derivatives were prepared by Suzuki reaction and bimolecular nucleophilic substitution. The compounds were tested against glioblastoma (U87MG) and melanoma (A375) tumor lines in the MTT and SRB assay. The cell death mechanism was evaluated by flow cytometry. The molecular modeling study was used to evaluate the interactions between the prepared compounds and the Bcl-xL protein. Results: Analogues presented IC50 values against glioblastoma lowe...

Molecules

Ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), and we previ... more Ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), and we previously showed that inactivation of OAT inhibits the growth of HCC. Recently, we found that (3S,4S)-3-amino-4-fluorocyclopentenecarboxylic acid (5) was a potent inactivator of γ-aminobutyric acid aminotransferase (GABA-AT), proceeding by an enamine mechanism. Here we describe our investigations into the activity and mechanism of 5 as an inactivator of human OAT. We have found that 5 exhibits 10-fold less inactivation efficiency (kinact/KI) against hOAT than GABA-AT. A comprehensive mechanistic study was carried out to understand its inactivation mechanism with hOAT. pKa and electrostatic potential calculations were performed to further support the notion that the α,β-unsaturated alkene of 5 is critical for enhancing acidity and nucleophilicity of the corresponding intermediates and ultimately responsible for the improved inactivation efficiency of 5 over the corresponding saturated analogu...

A doença de Chagas, causada pelo parasita Trypanosoma cruzi, acomete entre 6 a 8 milhões de pesso... more A doença de Chagas, causada pelo parasita Trypanosoma cruzi, acomete entre 6 a 8 milhões de pessoas em todo o mundo. Conhecida como tripanossomíase americana, por ter sido considerada endêmica apenas na América Latina, esta doença, se espalhou para outros continentes devido aos movimentos migratórios se tornando um problema de sáude mundial. Estima-se que 56.000 novos casos e cerca de 12.000 mortes por complicações relacionadas à doença de Chagas anualmente. A quimioterapia disponível para o tratamento é composta apenas por dois fármacos, nifurtimox e benznidazol, no entanto são pouco eficazes na fase crônica da doença. Estes fármacos apresentarem, ainda, efeitos adversos graves e resistência por parte de algumas cepas do parasita. Diante deste panorama, é iminente a necessidade da busca de novos fármacos contra T. cruzi. Para a busca racional de novos quimiterapicos antiparasitários é fundamental a identificação e caracterização de vias metabólicas essenciais à sobrevivência dos pa...

Human ornithine aminotransferase (hOAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme th... more Human ornithine aminotransferase (hOAT) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that contains a similar active site to that of γ-aminobutyric acid aminotransferase (GABA-AT). Recently, pharmacological inhibition of hOAT was recognized as a potential therapeutic approach for hepatocellular carcinoma. In this work, we first studied the inactivation mechanisms of hOAT by two well-known GABA-AT inactivators (CPP-115 and OV329). Inspired by the inactivation mechanistic difference between these two aminotransferases, a series of analogues were designed and synthesized, leading to the discovery of analogue 10b as a highly selective and potent hOAT inhibitor. Intact protein mass spectrometry, protein crystallography, and dialysis experiments indicated that 10b was converted to an irreversible tight-binding adduct (34) in the active site of hOAT, as was the unsaturated analogue (11). The comparison of kinetic studies between 10b and 11 suggested that the active intermediate (17b) was only generated in hOAT and not in GABA-AT. Molecular docking studies and pKa computational calculations highlighted the importance of chirality and the endocyclic double bond for inhibitory activity. The turnover mechanism of 10b was supported by mass spectrometric analysis of dissociable products and fluoride ion release experiments. Notably, the stopped-flow experiments were highly consistent with the proposed mechanism, suggesting a relatively slow hydrolysis rate for hOAT. The novel second-deprotonation mechanism of 10b contributes to its high potency and significantly enhanced selectivity for hOAT inhibition.

Agradeço primeiramente à Faculdade de Ciências Farmacêuticas (FCF/USP) pela oportunidade. À agênc... more Agradeço primeiramente à Faculdade de Ciências Farmacêuticas (FCF/USP) pela oportunidade. À agência de fomento, CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), pelo apoio financeiro. À todos os colaboradores deste trabalho, sem eles o trabalho não estaria completo. Aos professores da FCF/USP, que de uma maneira ou de outra contribuíram para o meu crescimento. Aos meus colegas do LITEC que são responsáveis por tudo, me ensinaram, ajudaram no que sabiam, e de uma forma especial, agradeço ao Prof. Dr. Vinícius Maltarollo que foi quem iniciou e finalizou todo esse trabalho junto comigo, me orientando e passando todos conhecimentos.

Acta Veterinaria Brno, 2013

Neonatal diarrhoea is a serious health problem on commercial farms. EnterovirulentEscherichia col... more Neonatal diarrhoea is a serious health problem on commercial farms. EnterovirulentEscherichia coliis a significant aetiological agent of neonatal diarrhoea. In this work, identification and classification ofE. coliisolates obtained from lambs and goat kids with diarrhoea were studied along with antibiotic resistance and clonal relationships of enterovirulent strains. A total of 107E. colistrains isolated from animals on 43 farms were investigated. Specific virulence genes were determined by multiplex and uniplex polymerase chain reaction. Testing of antibiotic susceptibility was carried out by the Vitek II compact system. The relationship ofE. coliisolates was determined by enterobacterial repetitive intergenic consensus polymerase chain reaction. A total of 39 (36.4%) enterovirulentE. colistrains were identified and of this 19 (48.7%) were shiga toxigenic, 12 (30.8%) enterotoxigenic and 8 (20.5%) enteropathogenic. Three isolates (7.7%) were found to be positive for extended spectru...

Pharmaceuticals

Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenet... more Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD+-dependent class III histone deacetylase, to interfere with the parasites’ cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC50 = 40 μM) was chosen as a potential lead compound.

Research, Society and Development, Nov 7, 2022

Exposure to pesticides and overweight-A systematic review Exposição a agrotóxicos e excesso de pe... more Exposure to pesticides and overweight-A systematic review Exposição a agrotóxicos e excesso de peso-Uma revisão sistemática Exposición a plaguicidas y sobrepeso-Una revisión sistemática

Journal of Chemical Information and Modeling

CERN European Organization for Nuclear Research - Zenodo, Jul 28, 2022

Scientific Reports

SARS-CoV-2’s papain-like protease (PLpro) interaction with ligands has recently been explored wit... more SARS-CoV-2’s papain-like protease (PLpro) interaction with ligands has recently been explored with a myriad of crystal structures. We used molecular dynamics (MD) simulations to study different PLpro-ligand complexes, their ligand-induced conformational changes, and interactions. We focused on inhibitors reported with known IC50 against PLpro, namely GRL-0617, XR8-89, PLP_Snyder530, and Sander’s recently published compound 7 (CPD7), and compared these trajectories against the apostructure (Apo), with a total of around 60 µs worth simulation data. We aimed to study the conformational changes using molecular dynamics simulations for the inhibitors in the PLpro. PCA analyses and the MSM models revealed distinct conformations of PLpro in the absence/presence of ligands and proposed that BL2-loop contributes to the accessibility of these inhibitors. Further, bulkier substituents closer to Tyr268 and Gln269 could improve inhibition of SARS-CoV-2 PLpro by occupying the region between BL2-g...

CERN European Organization for Nuclear Research - Zenodo, Jan 17, 2022

SARS-CoV-2's papain-like protease (PL pro) interaction with ligands has recently been explored wi... more SARS-CoV-2's papain-like protease (PL pro) interaction with ligands has recently been explored with a myriad of crystal structures. We used molecular dynamics (MD) simulations to study different PL pro-ligand complexes, their ligand-induced conformational changes, and interactions. We focused on inhibitors reported with known IC 50 against PL pro , namely GRL-0617, XR8-89, PLP_Snyder530, and Sander's recently published compound 7 (CPD7), and compared these trajectories against the apostructure (Apo), with a total of around 60 µs worth simulation data. We aimed to study the conformational changes using molecular dynamics simulations for the inhibitors in the PL pro. PCA analyses and the MSM models revealed distinct conformations of PL pro in the absence/presence of ligands and proposed that BL2-loop contributes to the accessibility of these inhibitors. Further, bulkier substituents closer to Tyr268 and Gln269 could improve inhibition of SARS-CoV-2 PL pro by occupying the region between BL2-groove and BL2-loop, but we also expand on the relevance of exploring multiple PL pro sub-pockets to improve inhibition. The recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 has been a worldwide concern since its first report in December 2019 (Wuhan, China). The disease caused by this new coronavirus was identified by the World Health Organization (WHO), in February 2020, as Coronavirus Disease 2019 (COVID-19). Later, the outbreak was declared a pandemic in March 2020, and, by January 2022, ~ 378 million cumulative cases were recorded globally, with ~ 5.67 million registered deaths 2. Researchers around the world have been working on developing preventive and therapeutic agents against SARS-CoV-2 3. Initially, eight vaccines were approved for full use, while the other six vaccines got approval for limited use against COVID-19 4,5. However, the emergence of SARS-CoV-2 variants led to increased transmission and resistance, which is associated with antibody escape from the virus spike epitopes. Currently, efficient clinical triage and supportive care are essential to contain severe COVID-19 patients 2. Despite the remarkable results of vaccination campaigns and the potential new drugs, in some countries, patients with COVID-19 are still treated with repurposed drugs. These drugs' effects are often controversial due to the adverse events or the lack of fully proven clinical verification of their therapeutic effects against this disease. Consequently, there is still a need for novel treatments, and the investigation of potential drug targets remains a cornerstone when designing novel antiviral drugs 6. Previous studies reported SARS-CoV-2's proteases as a source of attractive drug targets for antiviral development 7,8. The SARS-CoV-2 main protease (M pro) was the focus of studies due to the availability of crystal structures 9 and various groups have already exploited it for the development of inhibitors 10. Recently, PF-07321332, an inhibitor of the main protease (M pro), was an emergency use of authorization by the FDA against SARS-CoV-2 infection 6. On the other hand, the SARS-CoV-2 virus has a conserved Papain-like protease (PL pro) that is vital for viral replication 11. PL pro is responsible for the proteolytic processing of the product of open reading frame 1a (ORF1a) in the replicase gene of CoV-2, a large viral polyprotein containing non-structural proteins, which form the replicase complex 11,12. PL pro recognizes and cleaves the LXGG consensus sequence (Leu-X-Gly-Gly, X refers

Pharmaceutics

Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is high... more Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid ...

HDAC1 molecular dynamics simulations with co-crystallized ligand and proposed novel cinnamyl-hydr... more HDAC1 molecular dynamics simulations with co-crystallized ligand and proposed novel cinnamyl-hydroxamate anticancer agents. Details regarding the simulation method can be found in the respective publication.

Simulation Data related to the publication: Design, synthesis and biological activity of novel su... more Simulation Data related to the publication: Design, synthesis and biological activity of novel substituted 3-benzoic acid derivatives as MtDHFR inhibitors The files include raw trajectory files of the Desmond MD simulations of different MtDHFR inhibitors and substrates within the active site (trajectory format is out.cms and the full trj files, Schrödinger, LLC, New York, NY, 2019, more details on the materials and methods section of the respective publication). Article Abstract: The enzyme dihydrofolate reductase from M. tuberculosis (MtDHFR) have high untapped potential to be a target for new drugs against tuberculosis, due to its importance and uniqueness for this pathogen. Preliminary studies have obtained fragment-like molecules with low affinity to MtDHFR which can potentially become lead compounds. Taking this into account, the fragment MB872 was used as a prototyp...