MEDIATE - Molecular DockIng at homE: Turning collaborative simulations into therapeutic solutions.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

ProfhEX: AI-based platform for small molecules liability profiling.

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 R2 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/ .

Multidisciplinary Tumor Board Smart Virtual Assistant in Locally Advanced Cervical Cancer: A Proof of Concept.

AIM: 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. PATIENTS AND METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Development of a Microscale Thermophoresis-Based Method for Screening and Characterizing Inhibitors of the Methyl-Lysine Reader Protein MRG15.

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.

Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure.

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 3 H-benzo[ e][1,4]diazepine 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.