Computational approaches guiding for the design and optimization of novel chemo-types endowed with F508del-CFTR modulator ability

To date, monotherapy with VX-809 (Lumacaftor) or VX-770 (Ivacaftor) has not resulted in obvious clinical benefits for CF patients, while their combination regimen has provided positive results, stabilizing disease progress. Consequently, therapy combined with dual modulators or triple combination represents today the most promising prospect for developing new therapies. In this context, the research group in which I have been carrying out this thesis has dealt with rational design and computational studies of CFTR modulators during the past few years. The information obtained from our previous studies allowed us to proceed with the rational design and to predict the possible corrective activity of a new series of compounds with an aminoarylthiazole structure (AAT)1.,165. The previously proposed studies' reliability was supported by biological studies carried out on the newly synthesized molecules in collaboration with the research group led by Dr. Nicoletta Pedemonte (Istituto Giannina Gaslini, Genoa), verifying the corrective activity for F508del-CFTR of the newly designed derivatives. About the computational approaches so far applied, a QSAR model has been developed on the correctors available in literature guiding the following design and synthesis of hybrids compounds. This ligand-based method was used to overcome the paucity of information regarding a single and specific mechanism of action responsible for the corrective activity of VX-809. Indeed, as described in the literature, several hypotheses suggest multiple sites on the CFTR protein to which VX-809 could bind, first of all, the NBD1 domain. This thesis deepened the structure-based approach concerning various correctors described in the literature, including the hybrids developed by the present research group. In this context, experimental but partial data of the NBD1 domain of F508del-CFTR (PDB code: 4WZ6) were considered to perform molecular docking simulations of the compounds mentioned above. This research has been completed by molecular docking calculations performed on a whole model of the F508del-CFTR protein, which has been built in silico by our research group. Unlike what occurs for CFTR correctors, applying structure-based methods in the rational design of potentiators appears to be a more straightforward strategy since the experimental data concerning the binding mode of the VX-770 potentiator has recently become available (PDB code = 6O2P) and GLP1837 (PDB code = 6O1V). Starting from these assumptions, in this thesis, several libraries of compounds, described in the literature as CFTR potentiators, such as indoles, pyrazolquinolines, thienopyranes, cyanoquinolines, and AAT, have been studied to perform molecular docking studies and QSAR analysis activities. These approaches allowed us to obtain information to guide the rational design and future synthesis of new CFTR modulators. The research activity's further goal was to apply - in parallel to the studies just mentioned - ligand-based drug design analysis, using classical QSAR type analysis. This approach made it possible to overcome any limitation related to uniquely examining a single possible target for CFTR modulators and focusing on chemical scaffolds known today as correctors or potentiators

Multi-Party Media Partisanship Attention Score. Estimating Partisan Attention of News Media Sources Using Twitter Data in the Lead-up to 2018 Italian Election

The ongoing radical transformations in communication ecosystems have brought up concerns about the risks of partisan selective exposure and ideological polarization. Tra- ditionally, partisan selective exposure is measured by cross-tabulating survey responses to questions on vote intentions and media consumption. This process is expensive, limits the number of news outlets taken into account and is prone to the typical biases of self-reported data. Building upon previous works and with a specific focus on the online media environment, we introduce a new method to measure partisan media attention in a multi-party political system using Twitter data from 2018 Italian general election. Our first research question addresses the effectiveness of this method by measuring the extent to which our estimates correlate with partisan newspaper consumption measured by the latest Italian National Election Studies (ITANES) survey. Once established the reliability of our method, we employ these scores and measures to analyze the Italian digital media ecosystem in the lead-up to March 2018 election. The traditionally high level of political parallelism that characterizes both the Italian press and TV sectors is only partially reflected in a digital media ecosystem where partisan news sources seem to coexist with cross-partisan outlets. Results also point out that certain online partisan communities tend to rely more on exclusive news media sources

It takes a village to manipulate the media: coordinated link sharing behavior during 2018 and 2019 Italian elections.

Over the last few years, a proliferation of attempts to define, understand and fight the spread of problematic information in contemporary media ecosystems emerged. Most of these attempts focus on false content and/or bad actors detection. In this paper, we argue for a wider ecological focus. Using the frame of media manipulation and a revised version of the ‘coordinated inauthentic behavior’ original definition, the paper presents a study based on an unprecedented combination of Facebook data, accessed through the CrowdTangle API, and two datasets of Italian political news stories published in the run-up to the 2018 Italian general election and 2019 European election. By focusing on actors’ collective behavior, we identified several networks of pages, groups, and verified public profiles (‘entities’), that shared the same political news articles on Facebook within a very short period of time. Some entities in our networks were openly political, while others, despite sharing political content too, deceptively presented themselves as entertainment venues. The proportion of inauthentic entities in a network affects the wideness of the range of news media sources they shared, thus pointing to different strategies and possible motivations. The paper has both theoretical and empirical implications: it frames the concept of ‘coordinated inauthentic behavior’ in existing literature, introduces a method to detect coordinated link sharing behavior and points out different strategies and methods employed by networks of actors willing to manipulate the media and public opinion

Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays

open12Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride's mobilization in the epithelial cells of various organs. Recently a therapy focused on small molecules has been chosen as a main approach to contrast CF, designing and synthesizing compounds acting as misfolding (correctors) or defective channel gating (potentiators). Multi-drug therapies have been tested with different combinations of the two series of compounds. Previously, we designed and characterized two series of correctors, namely, hybrids, which were conceived including the aminoarylthiazole (AAT) core, merged with the benzodioxole carboxamide moiety featured by VX-809. In this paper, we herein proceeded with molecular modeling studies guiding the design of a new third series of hybrids, featuring structural variations at the thiazole moiety and modifications on position 4. These derivatives were tested in different assays including a YFP functional assay on models F508del-CFTR CFBE41o-cells, alone and in combination with VX-445, and by using electrophysiological techniques on human primary bronchial epithelia to demonstrate their F508del-CFTR corrector ability. This study is aimed (i) at identifying three molecules (9b, 9g, and 9j), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure-activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors.openParodi, Alice; Righetti, Giada; Pesce, Emanuela; Salis, Annalisa; Tomati, Valeria; Pastorino, Cristina; Tasso, Bruno; Benvenuti, Mirko; Damonte, Gianluca; Pedemonte, Nicoletta; Cichero, Elena; Millo, EnricoParodi, Alice; Righetti, Giada; Pesce, Emanuela; Salis, Annalisa; Tomati, Valeria; Pastorino, Cristina; Tasso, Bruno; Benvenuti, Mirko; Damonte, Gianluca; Pedemonte, Nicoletta; Cichero, Elena; Millo, Enric

New Insights into the Binding Features of F508del CFTR Potentiators: A Molecular Docking, Pharmacophore Mapping and QSAR Analysis Approach

Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. To combat this disease, many life-prolonging therapies are required and deeply investigated, including the development of the so-called cystic fibrosis transmembrane conductance regulator (CFTR) modulators, such as correctors and potentiators. Combination therapy with the two series of drugs led to the approval of several multi-drug effective treatments, such as Orkambi, and to the recent promising evaluation of the triple-combination Elexacaftor-Tezacaftor-Ivacaftor. This scenario enlightened the effectiveness of the multi-drug approach to pave the way for the discovery of novel therapeutic agents to contrast CF. The recent X-crystallographic data about the human CFTR in complex with the well-known potentiator Ivacaftor (VX-770) opened the possibility to apply a computational study aimed to explore the key features involved in the potentiator binding. Herein, we discussed molecular docking studies performed onto the chemotypes so far discussed in the literature as CFTR potentiator, reporting the most relevant interactions responsible for their mechanism of action, involving Van der Waals interactions and π–π stacking with F236, Y304, F305 and F312, as well as H-bonding F931, Y304, S308 and R933. This kind of positioning will stabilize the effective potentiator at the CFTR channel. These data have been accompanied by pharmacophore analyses, which promoted the design of novel derivatives endowed with a main (hetero)aromatic core connected to proper substituents, featuring H-bonding moieties. A highly predictive quantitative-structure activity relationship (QSAR) model has been developed, giving a cross-validated r2 (r2cv) = 0.74, a non-cross validated r2 (r2ncv) = 0.90, root mean square error (RMSE) = 0.347, and a test set r2 (r2pred) = 0.86. On the whole, the results are expected to gain useful information to guide the further development and optimization of new CFTR potentiators

DETECTING COORDINATED LINK SHARING BEHAVIOR ON FACEBOOK DURING THE ITALIAN CORONAVIRUS OUTBREAK

Social media, as many scholars have shown, can be used to influence political behavior through coordinated disinformation campaigns in which participants pretend to be ordinary citizens. With a specific reference to Facebook, a recent study has spotlighted patterns of coordinated activity aimed at fueling online circulation of specific news stories before the 2018 and 2019 Italian elections, an activity called by the authors “Coordinated Link Sharing Behavior” (CLSB). More precisely, CLSB refers to the coordinated shares of the same news articles in a very short time by networks of entities composed by Facebook pages, groups and verified public profiles. The uncertainty related to the coronavirus outbreak is a unique chance for malicious actors to leverage the anxiety of online publics to reach their goals, filling the information void with problematic content. Considering the association between coordination, media manipulation, and problematic information, the entities involved in coordinated online activities represent a privileged perspective on these phenomena. Thus, against the backdrop of the literature and the already conducted studies, this proposal will discuss Coordinated Link Sharing Behavior in the context of the coronavirus outbreak informational void, analyzing network mutations over time and the content strategies used to exploit the ambiguity associated with the topic

INTO THE BELLY OF THE BEAST: THE RESEARCH ON SOCIAL MEDIA AND COVID-19 MISINFORMATION IN 2020

In this paper we present some preliminary findings from an ongoing research on a comprehensive corpus of 378 interdisciplinary studies about misinformation and COVID-19 published in 2020, focusing on the role of social media platforms in spreading and countering mis- and disinformation. We followed the PRISMA guidelines for systematic reviews to collect and screen results, and a coding scheme based on methodological and substantive questions to analyze them. The preliminary results show, among others, that research on COVID-19 misinformation reproduces a well-known trend of differentiated attention to social media platforms based on both popularity among users and ease of access to data by scholars, that online survey distributed via social media has been a very popular approach, and the presence of a wide range of perspectives, and sometimes diverging point of views, on problematic information, in terms of prevalence of misinformation, countermeasures, and the role of social media communication. During the conference presentation, comprehensive results from the research will be presented

API AND BEYOND: DETECTING COORDINATED BEHAVIOURS IN FACEBOOK INTERACTIONS AROUND POLITICAL NEWS STORIES

This proposal is a follow-up of the project “Mapping Italian News Media Political Coverage in the Lead-up to 2018 General Election” (MINE). MINE aimed at creating a comprehensive map of the political news coverage created by the Italian online news media in the lead-up to 2018 general election. The final report of the project highlighted how the populist narrative dominated the news (both in terms of volume of coverage and Facebook engagement), and pinpointed the diverging patterns of Facebook interactions employed by different partisan communities to amplify the reach of the contents aligned with their worldview by sharing the news stories on social media, while trying to reframe, through comments, the negative coverage of the party they support. These insights led to further questions concerning the nature of the observed diverging patterns of Facebook interactions around political news. In particular, we wondered if the observed patterns were the result of a spontaneous grassroots effort or instead of a strategically organised attempt to manipulate the online news media landscape in order to game platforms algorithms in support of specific viewpoints, candidates and parties. Data originally collected for MINE during 2018 via publically available Facebook API proved useful to identify the patterns, but fall short of providing compelling evidence on the nature of these behaviours. In order to shed some light on this question, we thus requested and obtained access to two additional datasets directly provided by Facebook and made available through the Social Science One (SSO) initiative

At the onset of an infodemic: Geographic and disciplinary boundaries in researching problematic COVID-19 information

This paper analyzes the literature on problematic COVID-19 information published at the onset of the pandemic in 2020. It explores how scientific research has addressed this issue from a disciplinary, methodological and substantive perspective in different world regions. Three hundred seventy-eight articles were analyzed using content analysis and computational methods, including social network analysis and text mining. The study revealed a multidisciplinary field characterized by substantial contributions from medicine and social sciences and with a certain degree of interdisciplinarity and international collaborations. Research devoted particular attention to infodemic and conspiracy theories and their impact on compliance with health-protective behaviors, and showed a general preference for quantitative methods such as surveys. Most contributions focused on European and Americas regions and were from authors working in the same areas. Attention to various topics was also geographically differentiated. For example, conspiracy theories and informational factors that may influence COVID-compliant behaviors characterize the whole corpus, but Western research did the lion’s share. Similarly, the attention paid to different social media platforms differed geographically. Worldwide attention was dedicated to global social media platforms such as Twitter, WhatsApp, Facebook and Instagram. In contrast, geographically specific platforms (e.g., VKontakte or WeChat) have been studied less and mainly in regions where they are used the most. Focusing on a crucial period of the COVID-19 infodemic such as the first year of the pandemic, this study contributes to the literature on problematic information by highlighting how misinformation and disinformation research was carried out within and at the crossroads of disciplines and geographic regions. It suggests under-explored areas by contrast with the most relevant trends and establishes a foundation for benchmarking with post-2020 research on this topic.