| Abstract | Cilj: Cilj istraživanja je razviti nove inhibitore G3BP1/2, na temelju strukture poznatog inhibitora, N proteina SARS-CoV-2. Metode: U ovom istraživanju proučavana je kristalografska struktura G3BP proteina koristeći Protein Data Bank baze podataka, posebno strukture 7suo, 8th1 i 8v1l. Provedena je analiza vezivanja N proteina SARS-CoV-2 virusa na G3BP protein koristeći Discovery Studio, čime su identificirane ključne regije za interakciju. Na temelju dobivenih farmakofornih mapa izvršen je probir molekula pomoću ZINCPharmer servisa. Struktura proteina i liganada obrađena je u programima Chimera i Open Babel, a molekulsko sidrenje provedeno je korištenjem AutoDock Vina na superračunalu Supek. Validacija sidrenja izvršena je usporedbom RMSD vrijednosti između eksperimentalno potvrđenog inhibitora i najpovoljnije poze nakon sidrenja. Nakon toga, ChimeraX korišten je za vizualizaciju kompleksa, a PRED-hERG alat za predviđanje srčane toksičnosti liganada. Konačno, RDKit je upotrijebljen za procjenu fizikalno-kemijskih svojstava liganada, na temelju čega su odabrani najperspektivniji kandidati. Rezultati: U istraživanju je izdvojeno 20 liganada s najpovoljnijim afinitetom vezanja na G3BP protein. Najpovoljniji afiniteti vezanja, izuzimajući kardiotoksične ligande, su -11,11, -10,94 i -10,87, što je znatno bolje od eksperimentalno potvrđenog inhibitora G3BP (G3Ia) s afinitetom -6,11. Ti ligandi imaju molekulsku masu između 423,16 i 434,14 g/mol, dok G3Ia ima masu od 713,41 g/mol. LogP vrijednosti su 3,09, 4,39 i 4,10 u usporedbi s 2,99 liganda G3Ia. Najbolji ligandi imaju maksimalno 3 donora i 4 akceptora vodikovih veza, dok G3Ia ima 5 donora i 7 akceptora. Zaključak: Identificirano je 10 novih potencijalnih inhibitora G3BP1/2 s boljim afinitetom vezanja i fizikalno-kemijskim svojstvima od postojećih inhibitora G3Ia i G3Ib. Ove molekule predstavljaju obećavajuće kandidate za razvoj lijekova koji inhibiraju stvaranje stres granula, što bi moglo biti korisno u liječenju tumora i neurodegenerativnih bolesti. Daljnji koraci uključuju eksperimentalnu validaciju i optimizaciju ovih spojeva za terapijsku primjenu. |
| Abstract (english) | Objectives: The aim of this research is to develop new G3BP1/2 inhibitors based on the structure of known inhibitors, the N protein of the SARS-CoV-2. Methods: The crystallographic structure of the G3BP protein was studied using the Protein Data Bank database, focusing on the structures 7suo, 8th1, and 8v1l. Binding analysis of the N protein of the SARS-CoV-2 virus to the G3BP protein was conducted using Discovery Studio, identifying key interaction regions. Based on the obtained pharmacophore maps, molecule screening was performed using the ZINCPharmer service. The structure of proteins and ligands was processed using Chimera and Open Babel, and molecular docking was performed using AutoDock Vina on the Supek supercomputer. Docking validation was carried out by comparing RMSD values between the experimentally confirmed inhibitor and the most favorable positions after docking. ChimeraX was then used for visualizing the complexes, and the PRED-hERG tool was used to predict cardiac toxicity of the ligands. Finally, RDKit was employed to evaluate the physicochemical properties of the ligands, based on which the most promising candidates were selected. Results: The study identified 20 ligands with the most favorable binding affinity to the G3BP protein. The most favorable binding affinities, excluding cardiotoxic ligands, were -11.11, -10.94, and -10.87, significantly better than the experimentally confirmed G3BP inhibitor (G3Ia) with an affinity of -6.11. These ligands have a molecular weight between 423.16 and 434.14 g/mol, whereas G3Ia has a weight of 713.41 g/mol. Their logP values are 3.09, 4.39, and 4.10, compared to 2.99 for G3Ia. The best ligands have a maximum of 3 hydrogen bond donors and 4 acceptors, while G3Ia has 5 donors and 7 acceptors. Conclusion: Ten new potential G3BP1/2 inhibitors with more favorable binding affinity and physicochemical properties than existing inhibitors G3Ia and G3Ib have been identified. These molecules represent promising candidates for the development of drugs that inhibit stress granule formation, which could be beneficial in the treatment of tumors and neurodegenerative diseases. Further steps include experimental validation and optimization of these compounds for therapeutic application. |
