Combined ligand and structure based binding mode analysis of oxidosqualene cyclase inhibitors

The remarkable cyclization mechanism of the formation of the 6-6-6-5 tetracyclic lanosterol (a key triterpenoid intermediate in the biosynthesis of cholesterol) from the acyclic 2,3-oxidosqualene catalyzedb yo xidosqualenec yclase (OSC) has stimulated the interest of chemists and biologists for over ahalf century.Herein, the elaborate,state-of-the-art twodimensional (2D) QM/MM MD simulations have clearly shown that the cyclization of the A-C rings involves an early concerted, but highly asynchronous cyclization, to yield as table intermediate with "6-6-5" rings followed by the ring expansion of the C-ring concomitant with the formation of the D-ring to yield the "6-6-6-5" protosterol cation. The calculated reaction barrier of the rate-limiting step ( % 22 kcal mol À1 )i s comparable to the experimental kinetic results.Furthermore all previous experimental mutagenic evidence is highly consistent with the identified reaction mechanism.

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Biosynthetic Mechanism of Lanosterol: Cyclization

Chen

Wang

Smentek

et al. 2015

Angewandte Chemie

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show abstract

Biosynthetic Mechanism of Lanosterol: Cyclization

et al. 2015

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The remarkable cyclization mechanism of the formation of the 6-6-6-5 tetracyclic lanosterol (a key triterpenoid intermediate in the biosynthesis of cholesterol) from the acyclic 2,3-oxidosqualene catalyzed by oxidosqualene cyclase (OSC) has stimulated the interest of chemists and biologists for over a half century. Herein, the elaborate, state-of-the-art two-dimensional (2D) QM/MM MD simulations have clearly shown that the cyclization of the A-C rings involves a nearly concerted, but highly asynchronous cyclization, to yield a stable intermediate with "6-6-5" rings followed by the ring expansion of the C-ring concomitant with the formation of the D-ring to yield the "6-6-6-5" protosterol cation. The calculated reaction barrier of the rate-limiting step (≈22 kcal mol(-1)) is comparable to the experimental kinetic results. Furthermore all previous experimental mutagenic evidence is highly consistent with the identified reaction mechanism.

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Analysis of surface area features of structurally diverse molecules for Bcr/Abl kinase inhibitory activity and antiproliferative activity

et al. 2013

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Combined ligand and structure based binding mode analysis of oxidosqualene cyclase inhibitors

Cited by 5 publications

References 32 publications

Biosynthetic Mechanism of Lanosterol: Cyclization

Biosynthetic Mechanism of Lanosterol: Cyclization

Biosynthetic Mechanism of Lanosterol: Cyclization

Analysis of surface area features of structurally diverse molecules for Bcr/Abl kinase inhibitory activity and antiproliferative activity

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