Irina Moreira

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Verified

Irina verified their affiliation via an institutional email.

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• Ph.D
• Group Leader/Assistant Professor at University of Coimbra

We present SpotOn, a web server to identify and classify interfacial residues as Hot-Spots (HS) and Null-Spots (NS). SpotON implements a robust algorithm with a demonstrated accuracy of 0.95 and sensitivity of 0.98 on an independent test set. The predictor was developed using an ensemble machine learning approach with up-sampling of the minor class...

Background: Selectively targeting dopamine receptors (DRs) has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases involving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fu...

G-Protein Coupled Receptors (GPCR) are involved in a myriad of pathways key for human physiology through the formation of complexes with intracellular partners such as G-proteins and Arrestins (Arrs). However, the structural and dynamical determinants of these complexes are still largely unknown. Herein, we developed a computational big-data pipeli...

Globally with over 10 million deaths per year, cancer is the most transversal disease across countries, cultures, and ethnicities, affecting both developed and developing regions. Tumorigenesis is dynamically altered by distinct events and can be lethal when untreated. Despite the innovative therapeutics available, multidrug resistance (MDR) to che...

Understanding protein–protein interactions (PPIs) is fundamental to describe and to characterize the formation of biomolecular assemblies, and to establish the energetic principles underlying biological networks. One key aspect of these interfaces is the existence and prevalence of hot‐spots (HS) residues that, upon mutation to alanine, negatively...

Stargazin, a transmembrane AMPAR regulatory protein (TARP), plays a crucial role in facilitating the transport of AMPA receptors to the cell surface, stabilising their localisation at synapses and influencing their gating properties. The primary objective of this study was to investigate the effect of the V143L mutation in stargazin, previously lin...

G protein-coupled receptors (GPCRs) are key molecules involved in cellular signaling and are attractive targets for pharmacological intervention. This chapter is designed to explore the range of algorithms used to predict GPCRs’ activation states, while also examining the pharmaceutical implications of these predictions. Our primary objective is to...

G protein-coupled receptors (GPCRs) regulate cellular activity by transducing external signals and selectively coupling them to intracellular partners. Ghrelin receptor (GHSR) has garnered significant interest over the past decade owing to its diverse functional roles. In this study, we simulated five distinct GHSR–partner complexes, including Gq,...

The increase in the available G protein-coupled receptor (GPCR) structures has been pivotal in helping to understand their activation process. However, the role of protonation–conformation coupling in GPCR activation still needs to be clarified. We studied the protonation behavior of the highly conserved Asp2.50 residue in five different class A GP...

The current study shows that the accumulation of senescent brain endothelial cells (BECs) may mediate the transition from a young to an aged BBB. Aged BECs have a higher expression of senescent markers and impaired occludin expression which interferes with BBB function. These phenotypes were partially reverted after the systemic elimination of p16⁺...

The attrition rate of drugs in clinical trials is generally quite high, with estimates suggesting that approximately 90% of drugs fail to make it through the process. The identification of unexpected toxicity issues during preclinical stages is a significant factor contributing to this high rate of failure. These issues can have a major impact on t...

High-density lipoprotein (HDL) nanoparticles promote endothelial cell (EC) function and suppress inflammation, but their utility in treating EC dysfunction has not been fully explored. Here, we describe a fusion protein named ApoA1-ApoM (A1M) consisting of apolipoprotein A1 (ApoA1), the principal structural protein of HDL that forms lipid nanoparti...

Cell-penetrating peptides (CPPs) are short chains of amino acids that have shown remarkable potential to cross the cell membrane and deliver coupled therapeutic cargoes into cells. Designing and testing different CPPs to target specific cells or tissues is crucial to ensure high delivery efficiency and reduced toxicity. However, in vivo/in vitro te...

Motivation: Cancer is currently one of the most notorious diseases, with over one million deaths in the European Union alone in 2022. As each tumor can be composed of diverse cell types with distinct genotypes, cancer cells can acquire resistance to different compounds. Moreover, anticancer drugs can display severe side effects, compromising patie...

G protein-coupled receptors (GPCRs) are known to dimerize, but the molecular and structural basis of GPCR dimers is not well understood. In this study, we developed a computational framework to generate models of symmetric and asymmetric GPCR dimers using different monomer activation states and identified their most likely interfaces with molecular...

G protein-coupled receptors (GPCRs) mediate several signaling pathways through a general mechanism that involves their activation, upholding a chain of events that lead to the release of molecules responsible for cytoplasmic action and further regulation. These physiological functions can be severely altered by mutations in GPCR genes. GPCRs subfam...

DrugTax is an easy-to-use Python package for small molecule detailed characterization. It extends a previously explored chemical taxonomy making it ready-to-use in any Artificial Intelligence approach. DrugTax leverages small molecule representations as input in one of their most accessible and simple forms (SMILES) and allows the simultaneously ex...

Background: In cancer research, high-throughput screening technologies produce large amounts of multiomics data from different populations and cell types. However, analysis of such data encounters difficulties due to disease heterogeneity, further exacerbated by human biological complexity and genomic variability. The specific profile of cancer as...

Electroactive smart materials play an important role for tissue regenerative applications. Poly(vinylidene fluoride) (PVDF) is a specific subtype of piezoelectric electroactive material that generates electrical potential upon mechanical stimulation. This work focuses on the application of piezoelectric PVDF films for neural differentiation. Human...

Arrestins and G proteins are among the main intracellular partners of G‐Protein Coupled Receptors (GPCRs), a family of targets that represent 30–40% of total approved drugs. Depending on the subtype of partner or GPCR, different signaling pathways are triggered, with several physiological implications. We reviewed the main structural determinants i...

G Protein-Coupled Receptors (GPCRs) are the largest superfamily of proteins, able to perform a wide range of functions, depending on their specific sequence, three-dimensional (3D) structure, ligand-coupling, and subsequent signaling pathway. There is still a considerable number of questions that remain unanswered concerning their biological mechan...

Cells suffer from perturbations by different stimuli, which, consequently, rise to individual alterations in their profile and function that may end up affecting the tissue as a whole. This is no different if we consider the effect of a therapeutic agent on a biological system. As cells are exposed to external ligands their profile can change at di...

Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate a mutant form...

Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degen...

Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) is composed of four structural proteins and several accessory non-structural proteins. SARS-CoV-2’s most abundant structural protein, Membrane (M) protein, has a pivotal role both during viral infection cycle and host interferon antagonism. This is a highly conserved viral protein, thus a...

Viruses are a diverse biological group capable of infecting several hosts such as bacteria, plants, and animals, including humans. Viral infections constitute a threat to the human population as they may cause high mortality rates, decrease food production, and generate large economical losses. Viruses co-evolve with their hosts and this constant e...

SARS-CoV-2 triggered a worldwide pandemic disease, COVID-19, for which an effective treatment has not yet been settled. Among the most promising targets to fight this disease is SARS-CoV-2 main protease (Mpro), which has been extensively studied in the last few months. There is an urgency for developing effective computational protocols that can he...

Microglia modulate synaptic activity, essential for context-dependent cognitive performance, allowing organism-level adaptations to different environmental scenarios. Yet, the microglial molecular drivers required for synaptic remodeling related to cognitive performance remain largely elusive. Here, combining conditional gene targeting, single-cell...

Background Blood cancers (BCs) are responsible for over 720 K yearly deaths worldwide. Their prevalence and mortality-rate uphold the relevance of research related to BCs. Despite the availability of different resources establishing Disease-Disease Associations (DDAs), the knowledge is scattered and not accessible in a straightforward way to the sc...

This paper describes an exciting big data analysis compiled in a freely available database, which can be applied to characterize the coupling of different G-Protein coupled receptors (GPCRs) families with their intracellular partners. Opioid receptor (OR) family was used as case study in order to gain further insights into the physiological propert...

Text mining (TM) is a semi-automatized, multi-step process, able to turn unstructured into structured data. TM relevance has increased upon machine learning (ML) and deep learning (DL) algorithms’ application in its various steps. When applied to biomedical literature, text mining is named biomedical text mining and its specificity lies in both the...

Membrane proteins (MPs) encompass a large family of proteins with distinct cellular functions, and although representing over 50% of existing pharmaceutical drug targets, their structural and functional information is still very scarce. Over the last years, in silico analysis and algorithm development were essential to characterize MPs and overcome...

Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) is composed by four structural proteins and several accessory non-structural proteins. SARS-CoV-2's most abundant structural protein, Membrane (M) protein, has a pivotal role both during viral infection cycle and host interferon antagonism. This is a highly conserved viral protein, thus a...

Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) is composed by four structural proteins and several accessory non-structural proteins. SARS-CoV-2's most abundant structural protein, Membrane (M) protein, has a pivotal role both during viral infection cycle and host interferon antagonism. This is a highly conserved viral protein, thus a...

Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate an ID-associat...

High-throughput screening technologies continues to produce large amounts of multiomics data from different populations and cell types for various diseases, such as cancer. However, analysis of such data encounters difficulties due to cancer heterogeneity, further exacerbated by human biological complexity and genomic variability. There is a need t...

Membrane proteins (MPs) are key players in a variety of different cellular processes and constitute the target of around 60% of all Food and Drug Administration–approved drugs. Despite their importance, there is still a massive lack of relevant structural, biochemical and mechanistic information mainly due to their localization within the lipid bil...

Biological therapies, such as recombinant proteins, are nowadays amongst the most promising approaches towards precision medicine. One of the most innovative methodologies currently available aimed at improving the production yield of recombinant proteins with minimization of costs relies on the combination of in silico studies to predict and deepe...

This volume provides an overview of the current successes as well as pitfalls and caveats that are hindering the design of membrane proteins. Divided into six parts, chapters detail membrane transporter, FoldX force field, protein stability, G-Protein Coupled Receptors (GPCR) structures, transmembrane helices, membrane molecular dynamics (MD) simul...

Protein Hot-Spots (HS) are experimentally determined amino acids, key to small ligand binding and tend to be structural landmarks on protein–protein interactions. As such, they were extensively approached by structure-based Machine Learning (ML) prediction methods. However, the availability of a much larger array of protein sequences in comparison...

Targeting protein–protein interactions is a challenge and crucial task of the drug discovery process. A good starting point for rational drug design is the identification of hot spots (HS) at protein–protein interfaces, typically conserved residues that contribute most significantly to the binding. In this chapter, we depict point-by-point an in-ho...

Welcome From Chairs Dear colleagues worldwide, we are glad to invite you to MOL2NET-05, International Conference on Multidisciplinary Sciences, ISSN: 2624-5078, MDPI SciForum, Basel, Switzerland, 2019. MOL2NET is a year-round conference series with multiple associated workshops worldwide running and open to submissions almost all the year, please r...

Influenza (flu) is a contagious viral disease, which targets the human respiratory tract and spreads throughout the world each year. Every year, influenza infects around 10% of the world population and between 290,000 and 650,000 people die from it according to the World Health Organization (WHO). Influenza viruses belong to the Orthomyxoviridae fa...

GPCR oligomerization has emerged as a hot topic in the GPCR field in the last years. Receptors that are part of these oligomers can influence each other's function, although it is not yet entirely understood how these interactions work. The existence of such a highly complex network of interactions between GPCRs generates the possibility of alterna...

Our information‐driven docking approach HADDOCK has demonstrated a sustained performance since the start of its participation to CAPRI. This is due, in part, to its ability to integrate data into the modelling process, and to the robustness of its scoring function. We participated in CAPRI both as server and manual predictors. In CAPRI rounds 38‐45...

Human epidermal growth factor 2 (HER2) is a ligand-free tyrosine kinase receptor of the HER family that is overexpressed in some of the most aggressive tumours. Although it is known that HER2 dimerization involves a specific region of its extracellular domain, the so-called “dimerization arm”, the mechanism of dimerization inhibition remains uncert...

Human epidermal growth factor 2 (HER2) is a ligand-free tyrosine kinase receptor of the HER family that is overexpressed in some of the most aggressive tumours. Treatment of HER2+ breast cancers with the humanized monoclonal anti-HER2 antibody (Trastuzumab) revealed highly effective, encouraging the development of various HER2-specific antibodies,...

Our information-driven docking approach HADDOCK has demonstrated a sustained performance since the start of its participation to CAPRI. This is due, in part, to its ability to integrate data into the modelling process, and to the robustness of its scoring function. We participated in CAPRI both as server and as manual predictors. In CAPRI rounds 38...

Membrane proteins are essential vessels for cell communication both with other cells and noncellular structures. They modulate environment responses and mediate a myriad of biological processes. Dimerization and multimerization processes have been shown to further increase the already high specificity of these processes. Due to their central role i...

Membrane Proteins (MPs) account for around 15-39% of the human proteome and assume a critical role in a vast set of cellular and physiological mechanisms, including molecular transport, nutrient uptake, toxin and waste product clearance, respiration, and signaling. While roughly 60% of all FDA-approved drugs target MPs, there is a shortage of struc...

Background: Selectively targeting dopamine receptors has been a persistent challenge in the last years for the development of new treatments to combat the large variety of diseases evolving these receptors. Although, several drugs have been successfully brought to market, the subtype-specific binding mode on a molecular basis has not been fully elu...

Conference: Proceedings of the conference MOL2NET International Conference on Multidisciplinary Sciences (4th edition), 2018 is part of a year-round worldwide conference series hosted by MDPI Sciforum, Basel, Switzerland. This conference series has had organized more than 20 associated workshop series in universities worldwide: USA, France, Portuga...

Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To-Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abol...

Cancer has become one of the main leading causes of morbidity and mortality worldwide. One of the critical drawbacks of current cancer therapeutics has been the lack of the target-selectivity, as these drugs should have an effect exclusively on cancer cells while not perturbing healthy ones. In addition, their mechanism of action should be sufficie...

Parkinson’s Disease (PD) is a long-term neurodegenerative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel antiparkinsonian agents and an understanding of their proper and optimal u...

Background: Communication within a protein complex is mediated by physical interactions made among the protomers. Evidence for both the allosteric regulation present among the protomers of the protein oligomer and of the direct effect of membrane composition on this regulation has made it essential to investigate the underlying molecular mechanism...

Structural characterization of proteins and their complexes is a fundamental part in understanding any biological phenomena. Yet, the experimental determination of the three‐dimensional (3D) structure of proteins and their complexes remains a challenging undertaking. In order to complement the experimental approaches, computational methods have bee...

We present the performance of HADDOCK, our information-driven docking software, in the second edition of the D3R Grand Challenge. In this blind experiment, participants were requested to predict the structures and binding affinities of complexes between the Farnesoid X nuclear receptor and 102 different ligands. The models obtained in Stage1 with H...

Alzheimer’s Disease (AD) is one of the most common and complex age-related neurodegenerative disorders in elderly people. Currently there is no cure for AD, and available therapeutic alternatives only improve both cognitive and behavioral functions. For that reason, the search for anti-AD therapeutic agents with neuroprotective properties is highly...

Protein-protein interactions (PPIs) have proven necessary for the majority of biological processes, making their understanding vital for the development of new therapies and techniques in life sciences research. Among the residues that constitute a typical protein-protein interface, Hot-Spots (HS) are the most important ones due to their highly sta...

Background: Membrane proteins (MPs) play diverse and important functions in living organisms. They constitute 20% to 30% of the known bacterial, archaean and eukaryotic organisms' genomes. In humans, their importance is emphasized as they represent 50% of all known drug targets. Nevertheless, experimental determination of their three-dimensional (...

The identification of protein complexes and interactions is crucial for the understanding of cellular organization and machinery. Due to the high difficulty in attaining experimental data about such an important subject, computational tools and methodologies are emerging as reliable alternatives. It is especially true that Machine-Learning (ML) alg...

G protein-coupled receptors (GPCRs) are ubiquitously expressed transmembrane proteins associated with a wide range of diseases such as Alzheimer's, Parkinson, schizophrenia, and also implicated in in several abnormal heart conditions. As such, this family of receptors is regarded as excellent drug targets. However, due to the high number of intrace...

Proteins in the arrestin family exhibit a conserved structural fold that nevertheless allows for significant differences in their selectivity for G-protein-coupled-receptors (GPCRs) and their phosphorylation states. To reveal the mechanism of activation that prepares arrestin for selective interaction with GPCRs, and to understand the basis for the...

Understanding protein-protein interactions is a key challenge in biochemistry. In this work, we describe a more accurate methodology to predict Hot-Spots (HS) in protein-protein interfaces from their native complex structure compared to previous published Machine Learning (ML) techniques. Our model is trained on a large number of complexes and on a...

The General AMBER Force Field (GAFF) has been extended to describe a series of selenium and tellurium diphenyldichalcogenides. These compounds, besides being eco-friendly catalysts for numerous oxidations in organic chemistry, display peroxidase activity, i.e. can reduce hydrogen peroxide and harmful organic hydroperoxides to water/alcohols and as...

The natural tendency of proteins to bind to each other, as well as to many different molecules, forming stable and specific complexes is fundamental to all biological processes. The structural and functional description of protein-protein and protein-ligand complexes and their comprehension is a key concept, not only to increase the scientific know...

Biological systems rely on the establishment of interactions between biomolecules, which take place in the aqueous environment of the cell. It was already demonstrated that a small set of residues at the interface, Hot-Spots(HS), contributes significantly to the binding free energy. However, these energetic determinants of affinity and specificity...

Aiming to design (99m) Tc complexes for probing Nitric Oxide Synthase (NOS) by SPECT, we synthesized conjugates (L4 - L6) comprising a NOS-recognizing moiety connected to a diamino-propionic acid (dap) chelating unit. The conjugates led to complexes of the type fac-[M(CO)3 (ĸ(3) -L)] (M = Re/(99m) Tc; Re4/Tc4: L = L4; Re5/Tc5: L = L5; Re6/Tc6: L =...

Due to the importance of Hot-Spots (HS) detection and the efficiency of computational methodologies, several HS detecting approaches have been developed. The current paper is presenting new models to predict HS for protein-protein and protein-nucleic acid interactions with better statistics compared with the ones currently reported in literature. T...

Protein-protein (P-P) 3D structures are fundamental for structural biology and drug discovery. However, most of them have never been determined. Many docking algorithms were developed for that purpose, but they have a very limited accuracy in generating native-like structures and identifying the most correct one, in particular when a single answer...

Crystallographic structures of NGF/p75NTR and proNGF/p75NTR were previously obtained in 2:1 and 2:2 stoichiometries, respectively. However, evidence shows that both stoichiometries can occur for mature neurotrophins and pro-neurotrophins. We used Molecular Dynamics (MD) simulations to examine the energetic and structural characteristics of these tw...

A detailed comprehension of protein-based interfaces is essential for the rational drug development. One of the key features of these interfaces is their solvent accessible surface area profile. With that in mind, we tested a group of twelve SASA-based features for their ability to correlate and differentiate hot- and null-spots. These were tested...

Since the discovery of the first penicillin bacterial resistance to β-lactam antibiotics has spread and evolved promoting new resistances to pathogens. The most common mechanism of resistance is the production of β-lactamases that have spread thorough nature and evolve to complex phenotypes like CMT type enzymes. New antibiotics have been introduce...

Background: The details of the functional interaction between G proteins and the G protein coupled receptors (GPCRs) have long been subjected to extensive investigations with structural and functional assays and a large number of computational studies. Scope of review: The nature and sites of interaction in the G-protein/GPCR complexes, and the...

Background The details of the functional interaction between G proteins and the G protein coupled receptors (GPCRs) have long been subjected to extensive investigations with structural and functional assays and a large number of computational studies. Scope of review The nature and sites of interaction in the G-protein/GPCR complexes, and the spec...

The TEM family of enzymes has a crucial impact in the pharmaceutical industry due to their important role in antibiotic resistance. Even with the latest technologies in structural biology and genomics, no 3D structure of a TEM-1/Antibiotic complex is known previously to acylation. Therefore, the comprehension of their capability to acylate antibiot...

Considering our interest in the design of innovative radiometal-based complexes for in vivo imaging of nitric oxide synthase (NOS), we have recently introduced a set of M(CO)3-complexes (M=(99m)Tc, Re) containing a pendant N(ω)-NO2-l-arginine moiety, a known inhibitor of the enzyme. Enzymatic assays with purified inducible NOS have shown that the n...

Proteins and protein-based complexes are the basis of many key systems in nature and have been the subject of intense research in the last decades, in an attempt to acquire comprehensive knowledge of reactions that take place in nature. Computational Alanine Scanning Mutagenesis approaches have been extensively used in the study of protein interfac...