Ipitivanje konformacionih promena sirtuina 2 primenom simulacija molekulske dinamike

Abstract

Sirtuin 2 (Sirt2) se poslednjih godina sve više povezuje sa patogenezom kancera, neurodegeneracijom i inflamacijom zbog čega predstavlja atraktivan target za razvoj novih lekova. Većina do danas okarakterisanih inhibitora Sirt2 ne poseduje odgovarajuću aktivnost i/ili selektivnost. Kristalografske strukture objavljene u poslednjih par godina obezbedile su određeni pomak u razvoju novih inhibitora, međutim i dalje postoje nedoumice u vezi sa mehanizmom inhibicije koje su posledica visoke konformacone fleksibilnosti Sirt2 enzima. U cilju sticanja detaljnijeg uvida u konformacionu fleksibilnost Sirt2, izvedeno je sedamnaest simulacija molekulske dinamike u trajanju od po 100ns. Rezultati ove studije ukazali su na neke od ključnih rezidua neophodnih za stabilizaciju kompleksa Sirt2/inhibitor. Takođe, opisane konformacije daju jasniji uvid u katalitički ciklus deacilovanja. Opisan je i značaj konformacije kofaktorske petlje na konformaciju vezivnog mesta inhibitora. Rezultati ove studije će omogućiti racionalniji pristup dizajnu selektivnijih i potentnijih inhibitora sirtuina2.

Sirtuin 2 (Sirt2) has been implicated in pathogenesis of cancer, inflammation and neurodegeneration, which makes Sirt2 attractive target for development of novel therapeutics. A number of small molecule Sirt2 inhibitors have been reported, but most of them lack selectivity and/or high potency. Very recently published X-ray structures of selective ligand/Sirt2 complexes have revealed more details about mechanism of action of inhibitors, but some information still missing. Here, we will try to answer on questions regarding the conformational changes during enzyme catalysis, based on our recent molecular dynamic study of Sirt2. Total of seventeen 100 ns simulations have been performed on five different crystal structures. Results of this study have suggested one of key residues responsible for conformational stability of cofactor-binding loop and significant interaction with novel inhibitors. Further, “closing” of Sirt2 induced by presence of substrate has been described as major factor responsible for conformational changes in substrate-binding site. In conclusion, this study provides dynamic information on Sirt2 and may facilitate the rational design on novel, more potent and selective inhibitors.