Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been ...reported. Herein, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3H-benzoe1,4diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood–brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.
Off-target drug interactions are a major reason for candidate failure in the drug discovery process. Anticipating potential drug’s adverse effects in the early stages is necessary to minimize health ...risks to patients, animal testing, and economical costs. With the constantly increasing size of virtual screening libraries, AI-driven methods can be exploited as first-tier screening tools to provide liability estimation for drug candidates. In this work we present ProfhEX, an AI-driven suite of 46 OECD-compliant machine learning models that can profile small molecules on 7 relevant liability groups: cardiovascular, central nervous system, gastrointestinal, endocrine, renal, pulmonary and immune system toxicities. Experimental affinity data was collected from public and commercial data sources. The entire chemical space comprised 289′202 activity data for a total of 210′116 unique compounds, spanning over 46 targets with dataset sizes ranging from 819 to 18896. Gradient boosting and random forest algorithms were initially employed and ensembled for the selection of a champion model. Models were validated according to the OECD principles, including robust internal (cross validation, bootstrap, y-scrambling) and external validation. Champion models achieved an average Pearson correlation coefficient of 0.84 (SD of 0.05), an R
2
determination coefficient of 0.68 (SD = 0.1) and a root mean squared error of 0.69 (SD of 0.08). All liability groups showed good hit-detection power with an average enrichment factor at 5% of 13.1 (SD of 4.5) and AUC of 0.92 (SD of 0.05). Benchmarking against already existing tools demonstrated the predictive power of ProfhEX models for large-scale liability profiling. This platform will be further expanded with the inclusion of new targets and through complementary modelling approaches, such as structure and pharmacophore-based models. ProfhEX is freely accessible at the following address:
https://profhex.exscalate.eu/
.
The first prototype of the "Multidisciplinary Tumor Board Smart Virtual Assistant" is presented, aimed to (i) Automated classification of clinical stage starting from different free-text diagnostic ...reports; (ii) Resolution of inconsistencies by identifying controversial cases drawing the clinician's attention to particular cases worthy for multi-disciplinary discussion; (iii) Support environment for education and knowledge transfer to junior staff; (iv) Integrated data-driven decision making and standardized language and interpretation.
Data from patients affected by Locally Advanced Cervical Cancer (LACC), FIGO stage IB2-IVa, treated between 2015 and 2018 were extracted. Magnetic Resonance (MR), Gynecologic examination under general anesthesia (EAU), and Positron Emission Tomography-Computed Tomography (PET-CT) performed at the time of diagnosis were the items from the Electronic Health Records (eHRs) considered for analysis. An automated extraction of eHR that capture the patient's data before the diagnosis and then, through Natural Language Processing (NLP), analysis and categorization of all data to transform source information into structured data has been performed.
In the first round, the system has been used to retrieve all the eHR for the 96 patients with LACC. The system has been able to classify all patients belonging to the training set and - through the NLP procedures - the clinical features were analyzed and classified for each patient. A second important result was the setup of a predictive model to evaluate the patient's staging (accuracy of 94%). Lastly, we created a user-oriented operational tool targeting the MTB who are confronted with the challenge of large volumes of patients to be diagnosed in the most accurate way.
This is the first proof of concept concerning the possibility of creating a smart virtual assistant for the MTB. A significant benefit could come from the integration of these automated methods in the collaborative, crucial decision stages.
Collaborative computing has attracted great interest in the possibility of joining the efforts of researchers worldwide. Its relevance has further increased during the pandemic crisis since it allows ...for the strengthening of scientific collaborations while avoiding physical interactions. Thus, the E4C consortium presents the MEDIATE initiative which invited researchers to contribute via their virtual screening simulations that will be combined with AI-based consensus approaches to provide robust and method-independent predictions. The best compounds will be tested, and the biological results will be shared with the scientific community.
In this paper, the MEDIATE initiative is described. This shares compounds' libraries and protein structures prepared to perform standardized virtual screenings. Preliminary analyses are also reported which provide encouraging results emphasizing the MEDIATE initiative's capacity to identify active compounds.
Structure-based virtual screening is well-suited for collaborative projects provided that the participating researchers work on the same input file. Until now, such a strategy was rarely pursued and most initiatives in the field were organized as challenges. The MEDIATE platform is focused on SARS-CoV-2 targets but can be seen as a prototype which can be utilized to perform collaborative virtual screening campaigns in any therapeutic field by sharing the appropriate input files.
MRG15 is a transcription factor containing the methyl-lysine reader chromodomain. Despite its involvement in different physiological and pathological states, to date the role of this protein has not ...been fully elucidated due to the lack of a specific and potent chemical probe.
In this work, we report the development of a microscale thermophoresis (MST)-based assay for the study of MRG15–ligand binding interactions. After the development, the assay was validated using a small focused library and UNC1215 as the reference compound, to yield the identification of 10 MRG15 ligands with affinities ranging from 37.8 nM to 59.1 µM.
Hence, our method is robust, convenient, and fast and could be applied to other methylation reader domain-containing proteins for the identification of new chemical probes.
Collaborative computing has attracted great interest in the possibility of joining the efforts of researchers worldwide. Its relevance has further increased during the pandemic crisis since it allows ...for the strengthening of scientific collaborations while avoiding physical interactions. Thus, the E4C consortium presents the MEDIATE initiative which invited researchers to contribute via their virtual screening simulations that will be combined with AI-based consensus approaches to provide robust and method-independent predictions. The best compounds will be tested, and the biological results will be shared with the scientific community.
In this paper, the MEDIATE initiative is described. This shares compounds' libraries and protein structures prepared to perform standardized virtual screenings. Preliminary analyses are also reported which provide encouraging results emphasizing the MEDIATE initiative's capacity to identify active compounds.
Structure-based virtual screening is well-suited for collaborative projects provided that the participating researchers work on the same input file. Until now, such a strategy was rarely pursued and most initiatives in the field were organized as challenges. The MEDIATE platform is focused on SARS-CoV-2 targets but can be seen as a prototype which can be utilized to perform collaborative virtual screening campaigns in any therapeutic field by sharing the appropriate input files.
A theoretical approach for predicting the ultimate resistance of aluminium alloy members subjected to local buckling under uniform compression is presented focusing the attention on box sections. ...Starting from the J2 deformation theory of plasticity, the theory of plastic buckling of plates is presented including, as an original contribution, also the variability of the Poisson’s ratio depending on the stress levels. The differential equation of the plates at the onset of buckling is developed and the corresponding solution is provided. Starting from the obtained closed-form solution, the interactive buckling either in the elastic or in the plastic range is analysed. The interaction between the plate elements constituting the member section is explicitly accounted for using a completely theoretical approach where the evaluation of the critical stress leading to local buckling in the plastic range is derived as the value corresponding to the existence of a non-trivial solution for which the determinant of the matrix of the equation system is equal to zero. The accuracy of the plastic buckling theory is pointed out by comparing the buckling resistance obtained by the theoretical approach with the values of the ultimate resistance provided by stub column tests.
Finally, some advances concerning the use of the effective thickness approach, currently adopted by Eurocode 9, are also proposed and herein presented for the first time and compared with test results.
•Extension of the theory of plastic buckling of a single plate, including the variability of the Poisson’s ratio depending on the stress level.•Theoretical approach for predicting the ultimate resistance of aluminium members, considering the interaction between plate elements constituting the member section.•Comparison between the results obtained by the interactive procedure and the experimental stub tests presented in the scientific literature.•Application of the effective thickness method currently adopted by Eurocode 9.
•Prediction of local buckling resistance of aluminium angles by means of a theoretical procedure.•Definition of an analytical formulation to evaluate the interaction effects of the plate constituting ...the section.•Application of the advanced effective thickness method proposed in Annex L of prEN 1999–1-1.•Comparison between the experimental results with those obtained by the new methodologies: the Deformation Theory of Plasticity (DTP) and the Effective Thickness Method (ETM).•Analysis and comparison of the current design formulas in the evaluation of the ultimate compressive resistance of aluminium angles.
A theoretical approach for the evaluation of the ultimate resistance of aluminium angles subjected to local buckling under uniform compression is presented and compared with simplified approaches used for codification purposes. In particular, a theoretical procedure has been developed by considering the interaction of the outstand elements constituting the cross-section and the mechanical non-linearity of the material. To evaluate the accuracy of the theoretical approach, the results have been compared with experimental tests provided in the scientific literature. Then, a new mathematical formulation has been also derived to estimate the interaction effects of the section plates and it has been used for the extension of the Effective Thickness Method (ETM) according to the new version of Eurocode 9. Finally, the accuracy of simplified approaches as well is investigated by comparing the obtained values with the experimental results derived from the stub column tests reported in the scientific literature.
•12 experimental tests on box-shaped aluminium beams under non-uniform bending.•The material properties, failure modes, moment resistance, end rotation capacity and strain response of specimens have ...been reported.•Evaluation of local buckling effects on the ultimate resistance of aluminium beams.•Comparison between the experimental results with those obtained by means of current Eurocode provisions.•Evaluation of accuracy of the new approaches provided in the Annex L of the revised Eurocode 9.
The results of an experimental program dealing with SHS (Square Hollow Section) aluminium beams subjected to non-uniform bending are presented and discussed. Three-point bending tests have been performed on extruded SHS aluminium beams, made of 6060 alloy temper T66, with different width-to-thickness ratios. The material mechanical properties, the maximum flexural resistance, the rotation capability and the failure mode are reported in the manuscript. A finite element model is calibrated and validated against the force versus displacement experimental curves. Both the experimental and numerical results are compared with the current European design provisions, given in EN 1999-1-1. In particular, the different approaches suggested by EN 1999-1-1 are compared with the tests’ results.
The results obtained have shown that the ultimate resistance predicted by the codified provisions given in the general part of EN 1999-1-1 is, generally, on the safe side. Moreover, the refined effective thickness method (ETM) suggested in Annex L of revised EN 1999-1-1 is also applied. The refined method has shown higher accuracy in estimating the ultimate flexural resistance.
In this study, a theoretical investigation is conducted on the local buckling resistance of aluminium Z-sections subjected to uniform compression. A method is developed based on the J2 deformation ...theory of plasticity (DTP) to calculate the critical buckling load within the elastic–plastic range. The deformation theory of plasticity relies on the assumption that the strain state is uniquely defined by the stress state. Consequently, it serves as a specific path-independent non-linear constitutive model. The study commences with the elastoplastic differential equation for a single compressed plate. By incorporating the boundary conditions and the interaction between plate elements, the interactive buckling load is determined. An example is provided to illustrate the incremental nature of the numerical procedure. Additionally, numerical analyses are performed to examine the impact of the strain-hardening properties of aluminium alloys on local buckling resistance. In the final stage, the theoretical results are compared with those found in existing scientific literature. This comparison serves to evaluate the accuracy of the DTP procedure.
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