The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein-ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptorbinding domain of the Spike protein with high affinity and prevent ACE2 interaction. The World Health Organisation (WHO) declared the Coronavirus disease (COVID-19) outbreak a pandemic on March 12th 2020, and as of May 21st, over 4,893,186 cases and 323,256 deaths have been reported (https :// www.who.int/emerg encie s/disea ses/novel-coron aviru s-2019/situa tion-repor ts/). The Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) was identified as the viral agent causing the disease. SARS-CoV-2 is closely related to the SARS-CoV, which caused a pandemic in 2002-2003 1 , and it is believed to be the third member of the Coronaviridae family to cause severe respiratory diseases in human 2. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. SARS-CoV-2 has a single-stranded positive-sense RNA composed of 29,903 nt containing five genes, ORF1ab (codifying 16 non-structural proteins), spike (S), envelope (E), membrane (M) and nucleocapsid (N) genes 3. The virus uses the S homotrimeric glycoprotein located on the virion surface to allow entry into the human cells 4. The S protein goes through major structural rearrangements to mediate viral and human cell membranes fusion. The process is initiated by the binding of the receptor-binding domain (RBD) of the S1 subunit to the peptidase domain (PD) of angiotensin-converting enzyme 2 receptor (ACE2) on the host cell 5. Structural studies have shown that two S protein trimers can simultaneously bind to one ACE2 dimer 6. This induces a conformational change that expose a proteolytic site on the S protein, which is cleaved by the cellular serine protease TMPRSS2 7. Dissociation of S1 induces transition of the S2 subunit to a post fusion conformation, with exposed fusion peptides 8 , which allows endocytic entry of virus 9. Wrapp et ...

In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.

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It has been recently suggested that amino acid replacements with Gly can modify the shape of protein surfaces and, hence, protein dynamics and functions. We have browsed ClinVar, the database of all the reported variants of clinical relevance, to identify all the proteins having missense X/Gly mutations that determine Mendelian disorders. We have found 959 benign and 875 pathogenic X/Gly substitutions. Pathogenicity origins were initially searched in the distribution profiles of replaced amino acids. These profiles indicate that Mendelian disorders including Gly-replacements arise mainly from substitutions of amino acids bearing bulky hydrophobic side chains, thus reducing protein core stability. In the case mutated proteins were structurally defined, we could give a deeper insight into pathogenicity mechanisms, checking whether Gly-mutations altered protein shapes, modifying water surface dynamics and, hence, the physiological protein-protein interaction processes. In several cases, indeed, we have found that pathological Gly-mutants present additional surface pockets, suggesting that the new pockets could be the target of a pharmacological strategy for Mendelian disorder remediation.HighlightsClinVar has been scanned to find signals for pathogenicity due to X/Gly mutationsPathogenicity origins of X/Gly replacements have been structurally analyzedX/Gly mutations can create protein surface pockets with binding capabilitiesGly-formed new protein binding sites can be the target for Mendelian disorder curesAI procedures will expand the search for structural damages due to X/Gly mutationsGraphical abstract