IN SILICO FIZIČKO-HEMIJSKA, FARMAKOKINETIČKA I TOKSIKOLOŠKA ISPITIVANJA INHIBITORA 5-LIPOKSIGENAZE
Sažetak
Enzim 5-lipoksigenaza (5-LO) predstavlja važan enzim koji učestvuje u proizvodnji leukotriena, metabolita arahidonske kiseline pod čijim direktnim uticajem dolazi do razvoja reakcije inflamacije koja je povezana sa brojnim patofiziološkim stanjima. Stoga, otkrivanje i razvoj selektivnih 5-LO inhibitora za primenu u terapiji predstavljaju predmet istraživanja koja se trenutno sprovode. Cilj ove studije bio je da se najpre da pregled literature u vezi sa najaktivnijim sintetskim 5-LO inhibitorima (sa IC50 vrednostima manjim od 1 µM), usmeren prvenstveno na njihovu hemijsku strukturu, a potom predstave rezultati in silico studije njihovih osnovnih fizičko-hemijskih, farmakokinetičkih i toksikoloških karakteristika. Rezultati su pokazali da se fizičko-hemijski, farmakokinetički i toksikološki profili ispitivanih 5-LO inhibitora značajno razlikuju. Oko polovine ispitivanih 5-LO inhibitora ispunilo je „pravilo pet Lipinskog” i „pravilo Vebera”, što znači da je predviđena njihova dobra oralna bioraspoloživost. Takođe, predviđeno je da su posredi jedinjenja koja ne izazivaju mutagene, tumoralne, reproduktivne i/ili iritacione efekte. Sposobnost penetracije kroz Caco-2 ćelije, mogućnost intestinalne apsorpcije i mogućnost prolaska kroz krvno-moždanu barijeru predviđene su za mali broj ispitivanih jedinjenja. U suštini, povoljna fizičko-hemijska i toksikološka svojstva predviđena su za 32 od ukupno 99 testiranih jedinjenja. Sa najpovoljnijim farmakokinetičkim profilom izdvojio se derivat benzilidena 22.
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