Dizajn pirazolskih derivata vonoprazana kao potencijalnih reverzibilnih inhibitora protonske pumpe: in silico studija molekulskog dokinga
Sažetak
Uvod: Uprkos činjenici da se inhibitori protonske pumpe široko koriste za inhibiciju lučenja želudačne kiseline, nedavne studije su otkrile određene dugoročne neželjene efekte. Zbog kisele sredine u želucu, veliki je izazov dizajnirati nove kompetitivne inhibitore protonske pumpe sa snažnijom inhibicijom lučenja želudačne kiseline u poređenju sa konvencionalnim lekovima.
Cilj rada: Cilj ove in silico studije je bio da proceni potencijal odabranih derivata vonoprazana za inhibiciju protonske pumpe primenom studije molekulskog dokinga.
Metode: Dizajn pirazolskih derivata vonoprazana zasnovan na distribuciji sproveden je optimizacijom distribucionog koeficijenta na fiziološkoj pH vrednosti i pKa vrednosti. Studija molekulskog dokinga je sprovedena korišćenjem proteinske strukture protonske pumpe (PDB ID: 5YLU) u kompleksu sa vonoprazanom u softveru AutoDock Vina.
Rezultati: Prema procenjenim vrednostima doking skora, derivati 11, 21 i 25 pokazali su najveći afinitet prema protonskoj pumpi. Jedinjenja 3, 13, 14, 16, 17, 20, 22 i 23 formirala su najveći broj ključnih vezujućih interakcija sa aktivnim mestom protonske pumpe.
Zaključak: Na osnovu dobijenih parametara vezivanja, može se zaključiti da su derivati 14 i 23 nagradili najveći broj značajnih vezujućih interakcija (16, odnosno 15) uz istovremeno ostvarene niže vrednosti doking skora (-9.2 i -9.3 kcal/mol) u poređenju sa vonoprazanom kao kontrolom vezivanja. Na osnovu kriterijuma za procenu vezivanja, ova dva jedinjenja predstavljaju molekule sa najsnažnijim inhibitornim potencijalom prema protonskoj pumpi.
Reference
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