Navegando por Autor "Andrade, Carolina Horta"
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Item4D-QSAR: perspectives in drug design(2010) Andrade, Carolina Horta; Pasqualoto, Kerly Fernanda Mesquita; Ferreira, Elizabeth Igne; Hopfinger, Anton J.Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The quantitative structure–activity relationship (QSAR) formalisms are among the most important strategies that can be applied for the successful design new molecules. This review provides a comprehensive review on the evolution and current status of 4D-QSAR, highlighting present challenges and new opportunities in drug design. ItemCyclic voltammetry and computational chemistry studies on the evaluation of the redox behavior of parabens and other analogues(2012) Gil, Eric de Souza; Andrade, Carolina Horta; Barbosa, Núsia Luísa; Campos, Braga Rodolpho de; Serrano, Silvia Helena PiresParabens are antimicrobial preservatives widely used in pharmaceutical, cosmetic and food industries. The alkyl chain connected to the ester group defines some important physicochemical characteristics of these compounds, including the partition coefficient and redox properties. The voltammetric and computational analyses were carried out in order to evaluate the redox behavior of these compounds and other phenolic analogues. A strong correlation between chemical substituents inductive effects of parabens with redox potentials was observed. Using cyclic voltammetry and glassy carbon working electrode, only one irreversible anodic peak was observed around 0.8 V for methylparaben (MP), ethylparaben (EP), propylparaben (PP), butylparaben (BP), benzylparaben (BzP) and p-substituted phenolic analogues. The electrodonating inductive effect of alkyl groups was demonstrated by the anodic oxidation potential shift to lower values as the carbon number increases and, therefore the parabens (and other phenolic analogues) oxidation processes to the quinonoidic forms showed great dependence on the substituent pattern. ItemDihydroquinoline derivative as a potential anticancer agent: synthesis, crystal structure, and molecular modeling studies(2021) Vaz, Wesley Fonseca; Custodio, Jean Marcos Ferreira; D´Oliveira, Giulio Demetrius Creazzo; Neves, Bruno Junior; Carvalho Júnior, Paulo de Sousa; Moreira Filho, José Teófilo; Andrade, Carolina Horta; Noda Pérez, Caridad; Lacerda, Elisângela de Paula Silveira; Napolitano, Hamilton BarbosaCancer is one of the leading causes of death worldwide and requires intense and growing research investments from the public and private sectors. This is expected to lead to the development of new medicines. A determining factor in this process is the structural understanding of molecules with potential anticancer properties. Since the major compounds used in cancer therapies fail to encompass every spectrum of this disease, there is a clear need to research new molecules for this purpose. As it follows, we have studied the class of quinolinones that seem effective for such therapy. This paper describes the structural elucidation of a novel dihydroquinoline by single-crystal X-ray diffraction and spectroscopy characterization. Topology studies were carried through Hirshfeld surfaces analysis and molecular electrostatic potential map; electronic stability was evaluated from the calculated energy of frontier molecular orbitals. Additionally, in silico studies by molecular docking indicated that this dihydroquinoline could act as an anticancer agent due to their higher binding affinity with human aldehyde dehydrogenase 1A1 (ALDH 1A1). Tests in vitro were performed for VERO (normal human skin keratinocytes), B16F10 (mouse melanoma), and MDA-MB-231 (metastatic breast adenocarcinoma), and the results certified that compound as a potential anticancer agent. ItemEstudos de QSAR-3D para uma série de análogos à timidina com atividade tuberculostática(2011) Bueno, Renata Vieira; Braga, Rodolpho Campos; Toledo, Ney Ramos; Andrade, Carolina HortaTuberculosis (TB) is a chronic infectious disease with high epidemiological rates. The emergence of multidrug and extensively drug-resistant TB strains, as well as the long-term treatment and the side effects, become urgent the need for the development of new anti-tuberculosis drugs. Furthermore, the search for new targets is also necessary; as the current antimycobacterial drugs have just a small number of enzymes related to essential functions of the mycobacteria as targets. TMPKmt is an attractive target for the design of new antituberculosis agents since this enzyme is essential for DNA replication. In this work, we used the 3D-QSAR, by applying the Comparative Molecular Field Analysis (CoMFA), in order to elucidate the structural requirements relevant to the biological activity and to generate 3D-QSAR models for predicting the biological activity of compounds not yet synthesized, considering quantitative biological data and the interaction with TMPKmt of 106 thymidine analogues obtained from the literature. Robust and significant statistical models were obtained, confirming the importance of groups with higher electronic density and less bulky near ring 2. The studies herein developed with thymidine analogues through rational drug design lead to important data towards the search of new candidates as new anti-tuberculosis drugs. ItemIdentificação da desvenlafaxina, o principal metabólito da Vvnlafaxina, em cápsulas de liberação prolongada(Ricardo Menegatti, 2010-03) Carneiro, Wilsione Jose; Andrade, Carolina Horta; Braga, Rodolpho Campos; Oliveira, Valéria deIn this work, we describe the identification of desvenlafaxine in extended release capsules of venlafaxine (VEN) in acid degradation studies. We developed a stability indicating reverse-phase HPLC method and validated for the analysis of VEN in pharmaceutical formulation. The HPLC method was linear over the range of 0.45-1.05 mg/ml (r2=0.999). The RSD values for intra- and inter-day precision studies showed good results (RSD < 2%) and accuracy was greater than 99%. The degradation studies in acidic media for 24 h showed two additional peaks, which were further identified by ESI-MS/MS as the desvenlafaxine and the dehydration product of venlafaxine. Furthermore, desvenlafaxine is the major active metabolite of venlafaxine and has recently been approved for treatment of major depressive disorder. ItemIdentification of desvenlafaxine, the major active metabolite of venlafaxine, in extended-release capsules(Ricardo Menegatti, 2010-03) Carneiro, Wilsione Jose; Andrade, Carolina Horta; Braga, Rodolpho Campos; Oliveira, Valéria de ItemIn silico repositioning of new drugs against Schistosoma mansoni(Ruy de Souza Lino Junior, 2018-09) Bezerra, José Clecildo Barreto; Arantes, Morgana Elias; Andrade, Carolina Horta; Silva, Lourival Almeida; Neves, Bruno JuniorSchistosomiasis is a neglected tropical disease caused by parasites of the genus Schistosoma. In Brazil only Schistosoma mansoni causes this disease. The World Health Organization estimated in 2012 approximately 249 million people at risk of acquiring this disease around the world. The main strategy to control this disease is praziquantel treatment of individuals living in endemic areas. The drug praziquantel is used on a large scale in the treatment of schistosomiasis and currently there are reported cases of resistance, indicating the need to discover new drugs. In silico drug repositioning is a time and cost reducing strategy in the search for anti-Schistosoma agents. This work used bioinformatic tools to identify potential schistosomicidal drugs. A list was compiled of S. mansoni potential targets that are part of essential processes in the database TDR and the targets that are part of the tegument were obtained in the scientific literature. The file with S. mansoni targets contained 1,376 targets, and of these only 61 targets associated with 399 drugs had homology with drug targets. After removal of duplicate drugs, drugs found in previous studies and after the analysis of the conservation of the binding site, only 28 S. mansoni targets associated with 102 drugs had 60% or more of the active site conserved. Some of the drugs had activity and are interesting to validate this study such as: artemether, lumefantrine, meloxicam. Among the drugs found 18 drugs were selected to be tested in prospective experimental assays according to the following criteria: low toxicity in vivo, off-patent status, and logP <5.0. ItemIn silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni(2015-01) Neves, Bruno Junior; Braga, Rodolpho de Campos; Bezerra, José Clecildo Barreto; Cravo, Pedro Vitor Lemos; Andrade, Carolina HortaMorbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. ItemIn silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni(2015) Neves, Bruno Junior; Braga, Rodolpho de Campos; Bezerra, José Clecildo Barreto; Cravo, Pedro Vitor Lemos; Andrade, Carolina HortaMorbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. ItemIntegração de abordagens computacionais para identificar novos inibidores da proteína NS5 do vírus Zika(Universidade Federal de Goiás, 2020-12-14) Ramos, Paulo Ricardo Pimenta da Silva; Andrade, Carolina Horta; Andrade, Carolina Horta; Borba, Joyce Villa Verde Bastos; Neves, Bruno JuniorThe Zika virus (ZIKV), which caused recent outbreaks and epidemics in 2007, 2014 and 2015, is transmitted to humans mainly through the bite of female Aedes aegypti mosquitoes. In addition, transmission through blood, intercourse and lactation has been described in the literature. ZIKV infection has several consequences, mainly neurological serious, so far, there are no antivirals to fight infection or vaccines to prevent infection. Non-structural protein 5 (NS5), composed by the methyltransferase (MTase) and RNA polymerase (RdRP) domains, plays an essential role in the synthesis and stability of viral RNA, in addition to inhibiting the host's immune system, being a promising target for development of new antiviral. In this work, we perform the integration of computational approaches as quantitative structure activity relationships (QSAR) based on machine learning methods, molecular docking and search for similarity to identify new inhibitors of the NS5 protein from ZIKV. Due to the availability of data in the literature and the high sequential similarity between the NS5 sites of the dengue virus (DENV) and ZIKV, we initially searched for inhibitors of DENV NS5 protein in the PubChem and ChEMBL databases, to guide the screening of new NS5 inhibitors from ZIKV. 145 DENV NS5 inhibitors have been found in literature. We performed the virtual screening of these compounds using ZIKV phenotypic QSAR models. We also carry out molecular docking studies in the binding sites of the MTase and RdRP domains of ZIKV NS5. A total of 32 compounds were prioritized at this stage. Subsequently, a similarity search as performed in the commercial eMolecules database and the QSAR and docking steps were performed with the similar compounds. This analysis resulted in 4,953 similar compounds that also passed through the QSAR and docking filters. After this step, 176 compounds were selected as promising inhibitors of ZIKV NS5. We also submitted These compounds to Bayesian machine learning models to predict ZIKV activity and cytotoxicity, resulting in 44 compounds predicted to be active and non-cytotoxic to mammalian cells. These compounds were then submitted to the nAPOLI software for analysis of ligand-protein interactions. This step allowed the final selection of 14 promising compounds that will be acquired and experimentally validated, through ZIKV NS5 enzymatic assays and celular assays, that will be performed with collaborators. ItemMolecular modelling and optical properties of a novel fluorinated chalcone(2020) Custodio, Jean Marcos Ferreira; Guimarães Neto, J. J. A.; Awad, R.; Queiroz, J. E.; Verde, G. M. V.; Mottin, Melina; Neves, Bruno Junior; Andrade, Carolina Horta; Aquino, Gilberto Lúcio Benedito de; Valverde, Clodoaldo; Osorio, Francisco Aparecido Pinto; Baseia, Basilio; Napolitano, Hamilton BarbosaChalcones exhibit a broad spectrum of biological activities, mainly due to a,bunsaturated ketone, and are precursors of the biosynthesis of flavonoids present in plants. These compounds have been shown to be useful in the biological approach, proven by the broad spectrum of biological activities reported, and also in the technological approach, considering their potential as nonlinear optic (NLO) material. In this context, this work aimed to examine the crystallization and characterization of fluorinated chalcone (E)-1-(4-fluorophenyl)-3-(4-isopropylphenyl)prop-2-e n-1-one (DFC). A comprehensive structural study of DFC was carried out to understand the process of stabilizing the crystalline lattice through X-ray diffraction, infrared spectroscopy, and molecular modeling studies. Finally, the electrical properties of DFC were calculated by using the supermolecule method (SM). DFC molecules are connected by means of CAH O and CAH F intermolecular contacts, forming dimers which play an important role in the stabilization of crystal packing. Molecular modeling studies indicated that this compound could act as an anti-tuberculosis ligand because of its high binding affinity with the M. tuberculosis enoyl-acyl carrier protein, InhA. On the other hand, theoretical calculations were performed to evaluate the NLO properties of DFC and indicated that it showed good potential. ItemNatural products as leads in schistosome drug discovery(2015) Neves, Bruno Junior; Andrade, Carolina Horta; Cravo, Pedro Vitor LemosSchistosomiasis is a neglected parasitic tropical disease that claims around 200,000 human lives every year. Praziquantel (PZQ), the only drug recommended by the World Health Organization for the treatment and control of human schistosomiasis, is now facing the threat of drug resistance, indicating the urgent need for new effective compounds to treat this disease. Therefore, globally, there is renewed interest in natural products (NPs) as a starting point for drug discovery and development for schistosomiasis. Recent advances in genomics, proteomics, bioinformatics, and cheminformatics have brought about unprecedented opportunities for the rapid and more cost-effective discovery of new bioactive compounds against neglected tropical diseases. This review highlights the main contributions that NP drug discovery and development have made in the treatment of schistosomiasis and it discusses how integration with virtual screening (VS) strategies may contribute to accelerating the development of new schistosomidal leads, especially through the identification of unexplored, biologically active chemical scaffolds and structural optimization of NPs with previously established activity. ItemQSAR-driven design, synthesis and discovery of potent chalcone derivatives with antitubercular activity(2017) Gomes, Marcelo do Nascimento; Braga, Rodolpho de Campos; Grzelak, Edyta M.; Neves, Bruno Junior; Muratov, Eugene; Ma, Rui; Klein, Larry L.; Cho, Sang Hyun; Oliveira, Guilherme Roberto de; Franzblau, Scott Gary; Andrade, Carolina HortaNew anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6–12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17–20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 μM and <10 μM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11–545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents. ItemSynthesis, docking studies, pharmacological activity and toxicity of a novel pyrazole derivative (LQFM 021) - possible effects on phosphodiesterase(2013-05) Martins, Daniella Ramos; Pazini, Francine; Alves, Vinícius de Medeiros; Moura, Soraya Santana de; Liao, Luciano Morais; Magalhães, Mariana Torquato Quezado de; Valadares, Marize Campos; Andrade, Carolina Horta; Menegatti, Ricardo; Rocha, Matheus LavorentiThis study describes the synthetic route and molecular computational docking of LQFM 021, as well as examines its biological effects and toxicity. The docking studies revealed strong interaction of LQFM 021 to phosphodiesterase-3 (PDE-3). In isolated arteries, the presence of endothelium potentiates the relaxation for LQFM 021 and the inhibition cyclic nucleotides reduced the relaxation. Pre-contraction with KCl (45 mm), the treatment with tetraethylammonium (TEA) (5 mm) and inhibition of reticular Ca2+-ATPase showed an inhibitory effect on relaxation. Moreover, the compound reduced the contraction evoked by the Ca2+ influx. Acute toxicity tests revealed that the compound was practically nontoxic. In conclusion, this study showed that a new synthetic derivative of pyrazole is a possible PDE-3 inhibitor and has vasorelaxant activity and low toxicity ItemTwenty-six years of HIV science: an overview of anti-HIV drugs metabolism(2011-04) Andrade, Carolina Horta; Freitas, Lenis Medeiros de; Oliveira, Valéria deFrom the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.