Title Razvoj potencijalnih inhibitora nukleokapsidnog proteina koronavirusa SARS-CoV-2 Title (english) Development of potential inhibitors of SARS-CoV-2 coronavirus nucleocapsid protein Author Petar Gilić Kuko Mentor Dario Leskur (mentor)Committee member Ana Šešelja Perišin (predsjednik povjerenstva)Committee member Vedrana Čikeš Čulić (član povjerenstva)Committee member Josipa Bukić (član povjerenstva)Granter University of Split Defense date and country 2025-04-23, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Cilj istraživanja: Cilj ovog istraživanja bio je otkriti nove potencijalne inhibitore dimerizacijske domene nukleokapsidnog N proteina SARS-CoV-2 virusa primjenom računalnih metoda koje uključuju analizu kristalografske strukture proteina, identifikaciju veznog mjesta, izradu farmakoforne mape, virtualni probir spojeva, molekularno sidrenje, validaciju rezultata te procjenu kardiotoksičnosti i fizikalno-kemijskih svojstava odabranih liganada. Metode: Analizirana je kristalografska struktura dimerizacijske domene nukleokapsidnog proteina SARS CoV 2 virusa preuzeta iz Protein Data Bank baze podataka, kako bi se identificirala ključna vezna mjesta koristeći DoGSiteScorer. Na temelju dobivenih podataka izrađena je farmakoforna mapa korištenjem Discovery Studio 2024, koja je poslužila kao osnova za virtualni probir spojeva putem ZINCPharmer servisa. Receptor i ligandi obrađeni su u programima Chimera, Open Babel i Meeko, dok je molekularno sidrenje provedeno korištenjem AutoDock Vina. Validacija rezultata izvršena je usporedbom RMSD vrijednosti između različitih modela sidrenja u AutoDock Vina i AutoDock4. Za vizualizaciju kompleksa korišten je ChimeraX, a analiza interakcija obavljena je u Discovery Studio 2024. Predviđanje kardiotoksičnosti provedeno je pomoću PRED-hERG alata, dok su fizikalno-kemijska svojstva liganada kvantificirana uz pomoć RDKit-a. Rezultati: Virtualnim probirom identificirano je ukupno 787 molekula koje su zadovoljavale zadane farmakoforne kriterije. Nakon uklanjanja strukturnih duplikata preostalo je 470 jedinstvenih spojeva. Ovi spojevi rangirani su prema afinitetu vezanja, usklađenosti s Lipinski pravilom petice te predviđenoj odsutnosti kardiotoksičnih učinaka. Na temelju sveobuhvatne analize, odabrano je deset najperspektivnijih liganada za daljnja istraživanja, koji mogu biti osnova za potencijalna daljnja istraživanja i razvoj inhibitora nukleokapsidnog proteina SARS CoV 2. Zaključak: Rezultati istraživanja ukazuju na potencijal inhibicije dimerizacijske domene nukleokapsidnog proteina SARS CoV 2 kao nove strategije u borbi protiv virusa. Međutim, kako bi se utvrdila stvarna biološka učinkovitost i sigurnost ovih spojeva, potrebno je provesti opsežna in vitro i in vivo ispitivanja.
Abstract (english) Objectives: The aim of this research was to identify new potential inhibitors of the dimerization domain of the SARS-CoV-2 virus nucleocapsid N protein using computational methods, including analysis of the crystallographic structure of the protein, identification of the binding site, creation of a pharmacophore map, virtual screening of compounds, molecular docking, validation of results, and assessment of cardiotoxicity and physicochemical properties of the selected ligands. Methods: The crystallographic structure of the dimerization domain of SARS CoV 2 virus was obtained from the Protein Data Bank to identify critical binding sites using DoGSiteScorer. A pharmacophore model was generated based on these data using Discovery Studio 2024, and used as the basis for a virtual screening of compounds via the ZINCPharmer service. The receptor and ligands were processed using Chimera, Open Babel and Meeko, and molecular docking was performed with AutoDock Vina. Docking results were validated by comparing RMSD values across different models in AutoDock Vina and AutoDock4. Complex visualization was carried out using ChimeraX, while binding interactions were analyzed with Discovery Studio 2024. Potential cardiotoxicity was predicted using the PRED-hERG tool, and the physicochemical properties of the ligands were quantified with RDKit. Results: Through virtual screening, a total of 787 molecules were identified that satisfied the defined pharmacophore criteria. After removing structural duplicates, 470 compounds remained. These compounds were ranked according to binding affinity, compliance with Lipinski's Rule of Five, and predicted absence of cardiotoxic effects. Based on a comprehensive analysis, ten of the most promising ligands were chosen for the potential future development as specific inhibitors of the SARS CoV 2 nucleocapsid protein. Conclusion: The study results indicate a potential for targeting the dimerization domain of the SARS CoV 2 nucleocapsid protein as an innovative strategy against the virus. Nevertheless, extensive in vitro and in vivo evaluations are required to ascertain the true biological efficacy and safety of these compounds.
Keywords
nukleokapsidni protein
SARS-CoV-2
inhibitori
dimerizacijska domena
molekularno sidrenje
Keywords (english)
nucleocapsid protein
SARS-CoV-2
inhibitors
dimerization domain
molecular docking
Language croatian URN:NBN urn:nbn:hr:171:465608 Study programme Title: Pharmacy Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2025-04-24 07:00:34
