Rui M. M. Brito

University of Coimbra

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Carlos J. V. Simões

University of Coimbra

Pedro F. Cruz

University of Coimbra

Daniela C. Vaz

Instituto Politécnico de Leiria

Cândida G. Silva

Instituto Politécnico de Leiria

Zaida L. Almeida

University of Coimbra

Catarina S. H. Jesus

University of Coimbra

Paul R. Rosevear

University of Cincinnati

Maria João Saraiva

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

Tiago Q. Faria

Instituto de Biologia Experimental e Tecnológica

Joaquim Rui Rodrigues

Instituto Politécnico de Leiria

Cooperative Institutions

University of Coimbra

131

Universidade do Porto

University of Lisbon

Instituto Politécnico de Leiria

Universidade Nova de Lisboa

University of Minho

University of Aveiro

i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto

Centro de Neurociências e Biologia Celular

Rede de Química e Tecnologia

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A relational learning approach to Structure-Activity Relationships in drug design toxicity studies.

PubMed (2011)

Rui Camacho Max Pereira Vı́tor Santos Costa Nuno A. Fonseca Carlos Adriano

It has been recognized that the development of new therapeutic drugs is a complex and expensive process. A large number of factors affect the activity in vivo of putative candidate molecules and the propensity for causing adverse and toxic effects is recognized as one of the major hurdles behind the current "target-rich, lead-poor" scenario. Structure-Activity Relationship (SAR) studies, using relational Machine Learning (ML) algorithms, have already been shown to be very useful in the complex process of rational drug design. Despite the ML successes, human expertise is still of the utmost importance in the drug development process. An iterative process and tight integration between the models developed by ML algorithms and the know-how of medicinal chemistry experts would be a very useful symbiotic approach. In this paper we describe a software tool that achieves that goal--iLogCHEM. The tool allows the use of Relational Learners in the task of identifying molecules or molecular fragments with potential to produce toxic effects, and thus help in stream-lining drug design in silico. It also allows the expert to guide the search for useful molecules without the need to know the details of the algorithms used. The models produced by the algorithms may be visualized using a graphical interface, that is of common use amongst researchers in structural biology and medicinal chemistry. The graphical interface enables the expert to provide feedback to the learning system. The developed tool has also facilities to handle the similarity bias typical of large chemical databases. For that purpose the user can filter out similar compounds when assembling a data set. Additionally, we propose ways of providing background knowledge for Relational Learners using the results of Graph Mining algorithms.

Interface (matter)

Similarity (geometry)

10.2390/biecoll-jib-2011-182

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Citations (2)

The Tetrameric Protein Transthyretin Dissociates to a Non-native Monomer in Solution

Journal of Biological Chemistry (1999)

Alexandre Quintas Maria João Saraiva Rui M. M. Brito

In amyloidosis, normally innocuous soluble proteins polymerize to form insoluble fibrils. Amyloid fibril formation and deposition have been associated with a wide range of diseases, including spongiform encephalopathies, Alzheimer's disease, and familial amyloid polyneuropathies (FAP). In certain forms of FAP, the amyloid fibrils are mostly constituted by variants of transthyretin (TTR), a homotetrameric plasma protein implicated in the transport of thyroxine and retinol. The most common amyloidogenic TTR variant is V30M-TTR, and L55P-TTR is the variant associated with the most aggressive form of FAP. Recently, we reported that TTR dissociates to a monomeric species at pH 7.0 and nearly physiological ionic strengths (Quintas, A., Saraiva, M. J., and Brito, R. M. (1997) FEBS Lett.418, 297–300). Here, we show that the tetramer dissociation is apparently irreversible; and based on intrinsic tryptophan fluorescence and fluorescence quenching experiments, we show that the monomeric species formed upon tetramer dissociation is non-native. We also show, based on 1-anilino-8-naph-thalenesulfonate binding studies, that this monomeric species appears not to behave like a molten globule. These data allowed us to propose a model for TTR amyloidogenesis based on tetramer dissociation occurring naturally under commonly observed physiological solution conditions.

Tetramer

Amyloid disease

Amyloid (mycology)

10.1074/jbc.274.46.32943

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Citations (185)

DIBMA nanodiscs keep α-synuclein folded

Biochimica et Biophysica Acta (BBA) - Biomembranes (2020)

Regina Adão Pedro F. Cruz Daniela C. Vaz Fátima Fonseca Jannik Nedergaard Pedersen

10.1016/j.bbamem.2020.183314

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New self-assembled supramolecular hydrogels based on dehydropeptides

Journal of Materials Chemistry B (2015)

Helena Vilaça Goreti Pereira Tarsila G. Castro Bruno F. Hermenegildo Junfeng Shi

Supramolecular hydrogels rely on small molecules that self-assemble in water as a result of the cooperative effect of several relatively weak intermolecular interactions. Peptide-based low molecular weight hydrogelators have attracted enormous interest owing to the simplicity of small molecules combined with the versatility and biocompatibility of peptides. In this work, naproxen, a well known non-steroidal anti-inflammatory drug, was N-conjugated with various dehydrodipeptides to give aromatic peptide amphiphiles that resist proteolysis. Molecular dynamics simulations were used to obtain insight into the underlying molecular mechanism of self-assembly and to rationalize the design of this type of hydrogelators. The results obtained were in excellent agreement with the experimental observations. Only dehydrodipeptides having at least one aromatic amino acid gave hydrogels. The characterization of the hydrogels was carried out using transmission electron microscopy (TEM), circular dichroism (CD), fluorescence spectroscopy and also rheological assays.

10.1039/c5tb00501a

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Citations (34)

“Structural characterization of the minimal segment of TDP-43 competent for aggregation”

Archives of Biochemistry and Biophysics (2014)

Miguel Mompeán Emanuele Buratti Corrado Guarnaccia Rui M. M. Brito Avijit Chakrabartty

Heteronuclear molecule

Oligomer

Sequence (biology)

Conformational isomerism

10.1016/j.abb.2014.01.007

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Citations (75)

Lead optimization of resilient next-generation transthyretin stabilizers for multiple target-product profiles: approaching the CNS

Amyloid (2019)

Carlos J. V. Simões Zaida L. Almeida Ana L. Cardoso Filipa Bezerra Maria Rosário Almeida

"Lead optimization of resilient next-generation transthyretin stabilizers for multiple target-product profiles: approaching the CNS." Amyloid, 26(sup1), pp. 77–78

Lead (geology)

10.1080/13506129.2019.1583195

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Citations (2)

Targeting transthyretin amyloidosis in the eye with next-generation stabilizers: AT40 displays potent TTR stabilization in the human vitreous

Amyloid (2019)

Filipa Bezerra Carlos J. V. Simões João Melo Beirão Maria João Saraiva Rui M. M. Brito

"Targeting transthyretin amyloidosis in the eye with next-generation stabilizers: AT40 displays potent TTR stabilization in the human vitreous." Amyloid, 26(sup1), pp. 73–74

10.1080/13506129.2019.1583193

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Citations (2)

A molecular dynamics study of non-structural protein 1 (NS1) - a hub protein essential for influenza infection

F1000Research (2020)

Nícia Rosário‐Ferreira Rita Melo Carlos A.V. Barreto Irina S. Moreira Rui M. M. Brito

Open peer review

Dynamics

10.7490/f1000research.1117796.1

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Citations (0)

Enthalpic and entropic contributions mediate the role of disulfide bonds on the conformational stability of Interleukin‐4

Protein Science (2005)

Daniela C. Vaz Joaquim Rui Rodrigues Walter Sebald Christopher M. Dobson Rui M. M. Brito

Abstract The role of disulfide bridges in the structure, stability, and folding pathways of proteins has been the subject of wide interest in the fields of protein design and engineering. However, the relative importance of entropic and enthalpic contributions for the stabilization of proteins provided by disulfides is not always clear. Here, we perform a detailed analysis of the role of disulfides in the conformational stability of human Interleukin‐4 (IL4), a four‐helix bundle protein. In order to evaluate the contribution of two out of the three disulfides to the structure and stability of IL4, two IL4 mutants, C3T‐IL4 and C24T‐IL4, were used. NMR and ANS binding experiments were compatible with altered dynamics and an increase of the nonpolar solvent‐accessible surface area of the folded state of the mutant proteins. Chemical and thermal unfolding experiments followed by fluorescence and circular dichroism revealed that both mutant proteins have lower conformational stability than the wild‐type protein. Transition temperatures of unfolding decreased 14°C for C3T‐IL4 and 10°C for C24T‐IL4, when compared to WT‐IL4, and the conformational stability, at 25°C, decreased 4.9 kcal/mol for C3T‐IL4 and 3.2 kcal/mol for C24T‐IL4. Interestingly, both the enthalpy and the entropy of unfolding, at the transition temperature, decreased in the mutant proteins. Moreover, a smaller change in heat capacity of unfolding was also observed for the mutants. Thus, disulfide bridges in IL4 play a critical role in maintaining the thermodynamic stability and core packing of the helix bundle.

Protein Stability

10.1110/ps.051593306

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Citations (49)

Comparative NMR studies on cardiac troponin C and a mutant incapable of binding calcium at site II

Biochemistry (1991)

Rui M. M. Brito John A. Putkey N.C.J. Strynadka Michael N.G. James Paul R. Rosevear

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComparative NMR studies on cardiac troponin C and a mutant incapable of binding calcium at site IIRui M. M. Brito, John A. Putkey, Natalie C. J. Strynadka, Michael N. G. James, and Paul R. RosevearCite this: Biochemistry 1991, 30, 42, 10236–10245Publication Date (Print):October 1, 1991Publication History Published online1 May 2002Published inissue 1 October 1991https://pubs.acs.org/doi/10.1021/bi00106a023https://doi.org/10.1021/bi00106a023research-articleACS PublicationsRequest reuse permissionsArticle Views78Altmetric-Citations21LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Troponin C

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10.1021/bi00106a023

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Citations (28)