Yazar "Moreira, Irina Sousa" seçeneğine göre listele

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    Computational approaches in antibody-drug conjugate optimization for targeted cancer therapy
    (Bentham Science Publishers Ltd, 2018) Melo, Rita; Lemos, Agostinho; Preto, Antonio Jose; Almeida, Jose Guilherme; Correia, Joao D. G.; Şensoy, Özge; Moreira, Irina Sousa
    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 sufficiently fast to avoid the invasion of neighbouring healthy tissues by cancer cells. The use of conventional chemotherapeutic agents and other traditional therapies, such as surgery and radiotherapy, leads to off-target interactions with serious side effects. In this respect, recently developed target-selective Antibody-Drug Conjugates (ADCs) are more effective than traditional therapies, presumably due to their modular structures that combine many chemical properties simultaneously. In particular, ADCs are made up of three different units: a highly selective Monoclonal antibody (Mab) which is developed against a tumour-associated antigen, the payload (cytotoxic agent), and the linker. The latter should be stable in circulation while allowing the release of the cytotoxic agent in target cells. The modular nature of these drugs provides a platform to manipulate and improve selectivity and the toxicity of these molecules independently from each other. This in turn leads to generation of second-and third-generation ADCs, which have been more effective than the previous ones in terms of either selectivity or toxicity or both. Development of ADCs with improved efficacy requires knowledge at the atomic level regarding the structure and dynamics of the molecule. As such, we reviewed all the most recent computational methods used to attain all-atom description of the structure, energetics and dynamics of these systems. In particular, this includes homology modelling, molecular docking and refinement, atomistic and coarse-grained molecular dynamics simulations, principal component and cross-correlation analysis. The full characterization of the structure-activity relationship devoted to ADCs is critical for antibody-drug conjugate research and development.
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    Modulation of protein-protein interactions for the development of effective therapeutics - from a joint perspective of experiment and computation
    (Bentham Science Publishers B.V., 2018) Moreira, Irina Sousa; Şensoy, Özge
    Many proteins present in living organisms act as obligate oligomers – that is to say - they require other protein partners to function properly. Oligomerization does not only lead to the formation of physical interactions, which are required to hold individual protomers together in these assemblies, but it also triggers the cross-talk within the oligomer, so that individual protomers can regulate and modulate each other’s function in the form of either inhibition or activation. Consequently, this notion has changed the classical “single-target” pharmacology to “multi-target” one, urging the development of novel approaches in the field of drug discovery. In general, modulation of the function of a particular complex can be done by means of small-molecules developed specifically to target the interface between the protomers. This requires atomistic-level knowledge regarding the structure and dynamics of the system. As such, numerous experimental techniques were established in order to identify the partners in these assemblies. However, data solely based on these experimental techniques do not provide a mechanistic insight on the system as it cannot provide atomistic-level information per se regarding inherent allosteric interactions that govern the function of the complex. In this respect, computational methods act as indispensable tools to complement and to provide careful experimental data interpretation. The combination of these two worlds paves the way to the development of new, efficient and specific therapeutics.
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    Prediction and targeting of interaction interfaces in g-rotein coupled receptor oligomers
    (Bentham Science Publishers Ltd, 2018) Schiedel, Anke C.; Köse, Meryem; Barreto, Carlos; Bueschbell, Beatriz; Morra, Giulia; Şensoy, Özge; Moreira, Irina Sousa
    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 that drives oligomerization, the type of interactions present within the complex, and to determine the identity of the interaction interface. This knowledge allows a holistic understanding of dynamics and also modulation of the function of the resulting oligomers/signalling complexes. G-Protein-Coupled Receptors (GPCRs), which are targeted by 40% of currently prescribed drugs in the market, are widely involved in the formation of such physiological oligomers/signalling complexes. Scope: This review highlights the importance of studying Protein-Protein Interactions (PPI) by using a combination of data obtained from cutting-edge experimental and computational methods that were developed for this purpose. In particular, we focused on interaction interfaces found at GPCR oligomers as well as signalling complexes, since any problem associated with these interactions causes the onset of various crucial diseases. Conclusion: In order to have a holistic mechanistic understanding of allosteric PPIs that drive the formation of GPCR oligomers and also to determine the composition of interaction interfaces with respect to different membrane compositions, it is essential to combine both relevant experimental and computational data. In this way, efficient and specific targeting of these interaction interfaces in oligomers/complexes can be achieved. Thus, effective therapeutic molecules with fewer side effects can be designed to modulate the function of these physiologically important receptor family.
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    Understanding the differential selectivity of arrestins toward the phosphorylation state of the receptor
    (American Chemical Society, 2016) Şensoy, Özge; Moreira, Irina Sousa; Morra, Giulia
    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 these differences, we used unbiased molecular dynamics simulations to compare the structural and dynamic properties of wild type Arr1 (Arr1-WT), Arr3 (Arr3-WT), and a constitutively active Arr1 mutant, Arr1-R175E, characterized by a perturbation of the phosphate recognition region called "polar core". We find that in our simulations the mutant evolves toward a conformation that resembles the known preactivated structures of an Arr1 splice-variant, and the structurally similar phosphopeptide-bound Arr2-WT, while this does not happen for Arr1-WT. Hence, we propose an activation allosteric mechanism connecting the perturbation of the polar core to a global conformational change, including the relative reorientation of N- and C-domains, and the emergence of electrostatic properties of putative binding surfaces. The underlying local structural changes are interpreted as markers of the evolution of an arrestin structure toward an active-like conformation. Similar activation related changes occur in Arr3-WT in the absence of any perturbation of the polar core, suggesting that this system could spontaneously visit preactivated states in solution. This hypothesis is proposed to explain the lower selectivity of Arr3 toward nonphosphorylated receptors. Moreover, by elucidating the allosteric mechanism underlying activation, we identify functionally critical regions on arrestin structure that can be targeted with drugs or chemical tools for functional modulation.