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  1. Article ; Online: Computational approaches towards the discovery and optimisation of cruzain inhibitors.

    Santos, Viviane Corrêa / Ferreira, Rafaela Salgado

    Memorias do Instituto Oswaldo Cruz

    2022  Volume 117, Page(s) e210385

    Abstract: The need to develop safer and more efficacious drugs to treat Chagas disease has motivated the search for cruzain inhibitors. Cruzain is the recombinant, truncated version of cruzipain, a cysteine protease from Trypanosoma cruzi with important roles ... ...

    Abstract The need to develop safer and more efficacious drugs to treat Chagas disease has motivated the search for cruzain inhibitors. Cruzain is the recombinant, truncated version of cruzipain, a cysteine protease from Trypanosoma cruzi with important roles during the parasite life cycle. Several computational techniques have been applied to discover and optimise cruzain inhibitors, providing a molecular basis to guide this process. Here, we review some of the most recent computational studies that provided important information for the design of cruzain inhibitors. Moreover, we highlight the diversity of applications of in silico techniques and their impact.
    MeSH term(s) Cysteine Endopeptidases ; Cysteine Proteinase Inhibitors/pharmacology ; Protozoan Proteins ; Trypanosoma cruzi
    Chemical Substances Cysteine Proteinase Inhibitors ; Protozoan Proteins ; Cysteine Endopeptidases (EC 3.4.22.-) ; cruzipain (EC 3.4.22.51)
    Language English
    Publishing date 2022-03-16
    Publishing country Brazil
    Document type Journal Article ; Review
    ZDB-ID 953293-6
    ISSN 1678-8060 ; 0074-0276
    ISSN (online) 1678-8060
    ISSN 0074-0276
    DOI 10.1590/0074-02760210385
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: PyAutoFEP: An Automated Free Energy Perturbation Workflow for GROMACS Integrating Enhanced Sampling Methods.

    Carvalho Martins, Luan / Cino, Elio A / Ferreira, Rafaela Salgado

    Journal of chemical theory and computation

    2021  Volume 17, Issue 7, Page(s) 4262–4273

    Abstract: Free energy perturbation (FEP) calculations are now routinely used in drug discovery to estimate the relative FEB (RFEB) of small molecules to a biomolecular target of interest. Using enhanced sampling can improve the correlation between predictions and ... ...

    Abstract Free energy perturbation (FEP) calculations are now routinely used in drug discovery to estimate the relative FEB (RFEB) of small molecules to a biomolecular target of interest. Using enhanced sampling can improve the correlation between predictions and experimental data, especially in systems with conformational changes. Due to the large number of perturbations required in drug discovery campaigns, the manual setup of FEP calculations is no longer viable. Here, we introduce PyAutoFEP, a flexible and open-source tool to aid the setup of RFEB FEP. PyAutoFEP is written in Python3, and automates the generation of perturbation maps, dual topologies, system building and molecular dynamics (MD), and analysis. PyAutoFEP supports multiple force fields, incorporates replica exchange with solute tempering (REST) and replica exchange with solute scaling (REST2) enhanced sampling methods, and allows flexible λ values along perturbation windows. To validate PyAutoFEP, it was applied to a set of 14 Farnesoid X receptor ligands, a system included in the drug design data resource grand challenge 2. An 88% mean correct sign prediction was achieved, and 75% of the predictions had an error below 1.5 kcal/mol. Results using Amber03/GAFF, CHARMM36m/CGenFF, and OPLS-AA/M/LigParGen had Pearson's
    Language English
    Publishing date 2021-06-18
    Publishing country United States
    Document type Journal Article
    ISSN 1549-9626
    ISSN (online) 1549-9626
    DOI 10.1021/acs.jctc.1c00194
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Experimental and Computational Study of Aryl-thiosemicarbazones Inhibiting Cruzain Reveals Reversible Inhibition and a Stepwise Mechanism.

    Martins, Luan Carvalho / de Oliveira, Renata Barbosa / Lameira, Jerônimo / Ferreira, Rafaela Salgado

    Journal of chemical information and modeling

    2023  Volume 63, Issue 5, Page(s) 1506–1520

    Abstract: Trypanosoma ... ...

    Abstract Trypanosoma cruzi
    MeSH term(s) Humans ; Thiosemicarbazones/chemistry ; Thiosemicarbazones/pharmacology ; Cysteine Endopeptidases/chemistry ; Trypanosoma cruzi ; Chagas Disease ; Protozoan Proteins/chemistry ; Semicarbazones ; Cysteine Proteinase Inhibitors/chemistry
    Chemical Substances cruzipain (EC 3.4.22.51) ; Thiosemicarbazones ; Cysteine Endopeptidases (EC 3.4.22.-) ; Protozoan Proteins ; Semicarbazones ; Cysteine Proteinase Inhibitors
    Language English
    Publishing date 2023-02-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.2c01566
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Impact of different protonation states on virtual screening performance against cruzain.

    Santos, Viviane Corrêa / Campos, Augusto César Broilo / Waldner, Birgit J / Liedl, Klaus R / Ferreira, Rafaela Salgado

    Chemical biology & drug design

    2022  Volume 99, Issue 5, Page(s) 703–716

    Abstract: The cysteine protease cruzain is a Chagas disease target, exploited in computational studies. However, there is no consensus on the protonation states of the active site residues Cys25, His162, and Glu208 at the enzyme's active pH range. We evaluated the ...

    Abstract The cysteine protease cruzain is a Chagas disease target, exploited in computational studies. However, there is no consensus on the protonation states of the active site residues Cys25, His162, and Glu208 at the enzyme's active pH range. We evaluated the impact of different protonation states of these residues on docking calculations. Through a retrospective study with cruzain inhibitors and decoys, we compared the performance of virtual screening using four grids, varying protonation states of Cys25, His162, and Glu208. Based on enrichment factors and ROC plots, docking with the four grids affected compound ranking and the overall charge of top-ranking compounds. Different grids can be complementary and synergistic, increasing the odds of finding different ligands with diverse chemical properties.
    MeSH term(s) Cysteine Endopeptidases/chemistry ; Cysteine Proteases ; Protozoan Proteins/chemistry ; Retrospective Studies
    Chemical Substances Protozoan Proteins ; Cysteine Proteases (EC 3.4.-) ; Cysteine Endopeptidases (EC 3.4.22.-) ; cruzipain (EC 3.4.22.51)
    Language English
    Publishing date 2022-01-05
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2216600-2
    ISSN 1747-0285 ; 1747-0277
    ISSN (online) 1747-0285
    ISSN 1747-0277
    DOI 10.1111/cbdd.14008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Screening the Pathogen Box to Discover and Characterize New Cruzain and

    do Valle Moreira, Thales / Martins, Luan Carvalho / Diniz, Lucas Abreu / Bernardes, Talita Cristina Diniz / de Oliveira, Renata Barbosa / Ferreira, Rafaela Salgado

    Pathogens (Basel, Switzerland)

    2023  Volume 12, Issue 2

    Abstract: Chagas disease and Human African Trypanosomiasis, caused ... ...

    Abstract Chagas disease and Human African Trypanosomiasis, caused by
    Language English
    Publishing date 2023-02-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2695572-6
    ISSN 2076-0817
    ISSN 2076-0817
    DOI 10.3390/pathogens12020251
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Structure-based discovery of novel cruzain inhibitors with distinct trypanocidal activity profiles.

    Santos, Viviane Corrêa / Leite, Paulo Gaio / Santos, Lucianna Helene / Pascutti, Pedro Geraldo / Kolb, Peter / Machado, Fabiana Simão / Ferreira, Rafaela Salgado

    European journal of medicinal chemistry

    2023  Volume 257, Page(s) 115498

    Abstract: Over 110 years after the first formal description of Chagas disease, the trypanocidal drugs thus far available have limited efficacy and several side effects. This encourages the search for novel treatments that inhibit T. cruzi targets. One of the most ... ...

    Abstract Over 110 years after the first formal description of Chagas disease, the trypanocidal drugs thus far available have limited efficacy and several side effects. This encourages the search for novel treatments that inhibit T. cruzi targets. One of the most studied anti-T. cruzi targets is the cysteine protease cruzain; it is associated with metacyclogenesis, replication, and invasion of the host cells. We used computational techniques to identify novel molecular scaffolds that act as cruzain inhibitors. First, with a docking-based virtual screening, we identified compound 8, a competitive cruzain inhibitor with a K
    MeSH term(s) Humans ; Trypanosoma cruzi ; Cysteine Endopeptidases/pharmacology ; Chagas Disease/drug therapy ; Protozoan Proteins
    Chemical Substances cruzipain (EC 3.4.22.51) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Protozoan Proteins
    Language English
    Publishing date 2023-05-18
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2023.115498
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Insights into Substrate and Inhibitor Selectivity among Human GLUT Transporters through Comparative Modeling and Molecular Docking.

    Ferreira, Rafaela Salgado / Pons, Jean-Luc / Labesse, Gilles

    ACS omega

    2019  Volume 4, Issue 3, Page(s) 4748–4760

    Abstract: The solute carrier 2 family is composed of 14 transporters, which are members of the major facilitator superfamily. Despite their high physiological importance, there are still many open questions concerning their function and specificity, and in some ... ...

    Abstract The solute carrier 2 family is composed of 14 transporters, which are members of the major facilitator superfamily. Despite their high physiological importance, there are still many open questions concerning their function and specificity, and in some cases, their physiological substrate is still unknown. To understand the determinants of the substrate and inhibitor specificity, we modeled all human glucose transport carriers (GLUTs) and simulated their interaction with known ligands. Comparative modeling was performed with the @TOME-2 pipeline, employing multiple templates and providing an ensemble of models for each GLUT. We analyzed models in both outward-occluded and inward-open conformations, to compare exofacial and endofacial binding sites throughout the family and understand differences in susceptibility of GLUTs to the inhibitor cytochalasin B. Finally, we employed molecular docking and bioinformatics to identify residues likely critical for recognition of myo-inositol by GLUT13 and urate by GLUT9. These results provide insights into the molecular basis for the specificity for these substrates. In addition, we suggested a potential recognition site of glucosamine by GLUT11 to be evaluated in future experiments.
    Language English
    Publishing date 2019-03-04
    Publishing country United States
    Document type Journal Article
    ISSN 2470-1343
    ISSN (online) 2470-1343
    DOI 10.1021/acsomega.8b03447
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Aminopyrimidine Derivatives as Multiflavivirus Antiviral Compounds Identified from a Consensus Virtual Screening Approach.

    Serafim, Mateus Sá Magalhães / Kronenberger, Thales / Rocha, Rafael Eduardo Oliveira / Rosa, Amanda Del Rio Abreu / Mello, Thaysa Lara Gonçalves / Poso, Antti / Ferreira, Rafaela Salgado / Abrahão, Jonatas Santos / Kroon, Erna Geessien / Mota, Bruno Eduardo Fernandes / Maltarollo, Vinícius Gonçalves

    Journal of chemical information and modeling

    2024  Volume 64, Issue 2, Page(s) 393–411

    Abstract: Around three billion people are at risk of infection by the dengue virus (DENV) and potentially other flaviviruses. Worldwide outbreaks of DENV, Zika virus (ZIKV), and yellow fever virus (YFV), the lack of antiviral drugs, and limitations on vaccine ... ...

    Abstract Around three billion people are at risk of infection by the dengue virus (DENV) and potentially other flaviviruses. Worldwide outbreaks of DENV, Zika virus (ZIKV), and yellow fever virus (YFV), the lack of antiviral drugs, and limitations on vaccine usage emphasize the need for novel antiviral research. Here, we propose a consensus virtual screening approach to discover potential protease inhibitors (NS3
    MeSH term(s) Humans ; Zika Virus ; Zika Virus Infection ; Molecular Docking Simulation ; Consensus ; Flavivirus ; Antiviral Agents/chemistry ; Pyrimidines
    Chemical Substances 2-aminopyrimidine (109-12-6) ; Antiviral Agents ; Pyrimidines
    Language English
    Publishing date 2024-01-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.3c01505
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Design and synthesis of new 1,2,3-triazoles derived from eugenol and analogues with in vitro and in vivo activity against Trypanosoma cruzi.

    Reis, Rúbia Castro Fernandes Melo / Dos Santos, Elda Gonçalves / Benedetti, Monique Dias / Reis, Adriana Cotta Cardoso / Brandão, Geraldo Célio / Silva, Glenda Nicioli da / Diniz, Lucas Abreu / Ferreira, Rafaela Salgado / Caldas, Ivo Santana / Braga, Saulo Fehelberg Pinto / Souza, Thiago Belarmino de

    European journal of medicinal chemistry

    2023  Volume 258, Page(s) 115622

    Abstract: Chagas disease (CD) is a neglected tropical disease endemic in 21 countries and affects about 8 million people around the world. The pharmacotherapy for this disease is limited to two drugs (Benznidazole and Nifurtimox) and both are associated with ... ...

    Abstract Chagas disease (CD) is a neglected tropical disease endemic in 21 countries and affects about 8 million people around the world. The pharmacotherapy for this disease is limited to two drugs (Benznidazole and Nifurtimox) and both are associated with important limitations, as low cure rate in the chronic phase of the disease, high toxicity and increasing resistance by Trypanosoma cruzi. Recently, we reported a bioactive 1,2,3-triazole (compound 35) active in vitro (IC
    MeSH term(s) Mice ; Rats ; Animals ; Trypanosoma cruzi ; Eugenol/pharmacology ; Triazoles/pharmacology ; Triazoles/therapeutic use ; Parasitemia/drug therapy ; Trypanocidal Agents/toxicity ; Chagas Disease/drug therapy
    Chemical Substances benzonidazole (YC42NRJ1ZD) ; Eugenol (3T8H1794QW) ; Triazoles ; Trypanocidal Agents
    Language English
    Publishing date 2023-07-11
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2023.115622
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Structure-based Approaches Targeting Parasite Cysteine Proteases.

    Vieira, Rafael Pinto / Santos, Viviane Corrêa / Ferreira, Rafaela Salgado

    Current medicinal chemistry

    2017  Volume 26, Issue 23, Page(s) 4435–4453

    Abstract: Cysteine proteases are essential hydrolytic enzymes present in the majority of organisms, including viruses and unicellular parasites. Despite the high sequence identity displayed among these proteins, specific structural features across different ... ...

    Abstract Cysteine proteases are essential hydrolytic enzymes present in the majority of organisms, including viruses and unicellular parasites. Despite the high sequence identity displayed among these proteins, specific structural features across different species grant distinct functions to these biomolecules, frequently related to pathological conditions. Consequently, their relevance as promising targets for potential specific inhibitors has been highlighted and occasionally validated in recent decades. In this review, we discuss the recent outcomes of structure-based campaigns aiming the discovery of new inhibitor prototypes against cruzain and falcipain, as alternative therapeutic tools for Chagas disease and malaria treatments, respectively. Computational and synthetic approaches have been combined on hit optimization strategies and are also discussed herein. These rationales are extended to additional tropical infectious and neglected pathologies, such as schistosomiasis, leishmaniasis and babesiosis, and also to Alzheimer's Disease, a widespread neurodegenerative disease poorly managed by currently available drugs and recently linked to particular physiopathological roles of human cysteine proteases.
    MeSH term(s) Animals ; Cysteine Proteases/metabolism ; Cysteine Proteinase Inhibitors/chemical synthesis ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/pharmacology ; Humans ; Models, Molecular ; Molecular Structure
    Chemical Substances Cysteine Proteinase Inhibitors ; Cysteine Proteases (EC 3.4.-)
    Language English
    Publishing date 2017-08-04
    Publishing country United Arab Emirates
    Document type Journal Article ; Review
    ZDB-ID 1319315-6
    ISSN 1875-533X ; 0929-8673
    ISSN (online) 1875-533X
    ISSN 0929-8673
    DOI 10.2174/0929867324666170810165302
    Database MEDical Literature Analysis and Retrieval System OnLINE

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