ABSTRACT In December 2019, in Wuhan, China, a new coronavirus was identified for the first time, currently known worldwide as SARS-CoV-2, responsible for the pandemic identified with the initials COVID-19. Following the entry of the virus into the host cell, a severe acute respiratory syndrome develops with a consequent increase in the inflammatory response. Despite the short-term appearance of several experimental vaccines to prevent COVID-19, to date there is still no targeted treatment to block the infectivity of the SARS-CoV-2 virus. One of the crucial aspects on which many scientific studies are based is the characterization of the three-dimensional structure of the constituent proteins SARS-CoV-2, in order to understand mechanisms such as replication, transcription and assembly of the viral genome, as well as the entry of the virus inside the host cell. The goal of this thesis was to investigate the structural characteristics of the protein ORF3A and E, two viroporins having a key role in the replication of the SARS-CoV-2 virus within the host cell. With the aid of "open-source" programs, such as MGLTools, Autodock and Pymol, a virtual computational screening was carried out on thousands of molecules present in the database of drugs already approved by the US drug agency (FDA), in order to to identify molecules and ligands, having a high binding affinity for the ORF3A protein and for the E protein, able to be perfectly placed inside the channel proteins, temporarily blocking their activity and thus preventing the entry of the virus inside the host cell. The results obtained show how the development of increasingly targeted drugs capable of blocking the functional activity of the proteins mentioned above, represents a valid therapeutic strategy to counter and prevent the worldwide SARS-CoV-2 pandemic.
ABSTRACT Nel dicembre 2019, a Wuhan, in Cina, è stato identificato per la prima volta un nuovo coronavirus, attualmente noto nel mondo come SARS-CoV-2, responsabile della pandemia identificata con la sigla COVID-19. In seguito all’ingresso del virus nella cellula ospite, si ha lo sviluppo di una severa sindrome respiratoria acuta con un conseguente incremento della risposta infiammatoria. Nonostante la comparsa in breve tempo di diversi vaccini sperimentali per prevenire il COVID-19, ad oggi non esiste ancora un trattamento mirato per bloccare l’infettività del virus SARS-CoV-2. Uno degli aspetti cruciali su cui si basano molti studi scientifici è la caratterizzazione della struttura tridimensionale delle proteine costituenti SARS-CoV-2, al fine di comprendere meccanismi quali la replicazione, la trascrizione e l’assemblaggio del genoma virale, nonché l’ingresso del virus all’interno della cellula ospite. L’obiettivo di questo lavoro di tesi è stato quello di indagare le caratteristiche strutturali della proteina ORF3A ed E, due viroporine aventi un ruolo chiave nella replicazione del virus SARS-CoV-2 all’interno della cellula ospite. Tramite l’ausilio di programmi “open-source”, quali MGLTools, Autodock e Pymol, è stato effettuato uno screening computazionale virtuale su migliaia di molecole presenti nella banca data dei farmaci già approvati dall’agenzia del farmaco statunitense (FDA), al fine di individuare molecole e ligandi, aventi un’elevata affinità di legame per la proteina ORF3A e per la proteina E, in grado di collocarsi perfettamente all’interno delle proteine canale, bloccandone temporaneamente l’attività e prevenendone in tal modo l’ingresso del virus all’interno della cellula ospite. I risultati ottenuti dimostrano come lo sviluppo di farmaci sempre più mirati ed in grado di bloccare l’attività funzionale delle proteine sopra citate, rappresenti una valida strategia terapeutica per contrastare e prevenire la pandemia mondiale da SARS-CoV-2.
Screening in silico di farmaci FDA su canali ionici del virus SARS-CoV-2 a scopo terapeutico
CHIRCO, GIUSEPPE
2020/2021
Abstract
ABSTRACT In December 2019, in Wuhan, China, a new coronavirus was identified for the first time, currently known worldwide as SARS-CoV-2, responsible for the pandemic identified with the initials COVID-19. Following the entry of the virus into the host cell, a severe acute respiratory syndrome develops with a consequent increase in the inflammatory response. Despite the short-term appearance of several experimental vaccines to prevent COVID-19, to date there is still no targeted treatment to block the infectivity of the SARS-CoV-2 virus. One of the crucial aspects on which many scientific studies are based is the characterization of the three-dimensional structure of the constituent proteins SARS-CoV-2, in order to understand mechanisms such as replication, transcription and assembly of the viral genome, as well as the entry of the virus inside the host cell. The goal of this thesis was to investigate the structural characteristics of the protein ORF3A and E, two viroporins having a key role in the replication of the SARS-CoV-2 virus within the host cell. With the aid of "open-source" programs, such as MGLTools, Autodock and Pymol, a virtual computational screening was carried out on thousands of molecules present in the database of drugs already approved by the US drug agency (FDA), in order to to identify molecules and ligands, having a high binding affinity for the ORF3A protein and for the E protein, able to be perfectly placed inside the channel proteins, temporarily blocking their activity and thus preventing the entry of the virus inside the host cell. The results obtained show how the development of increasingly targeted drugs capable of blocking the functional activity of the proteins mentioned above, represents a valid therapeutic strategy to counter and prevent the worldwide SARS-CoV-2 pandemic.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/13752