Insight into the Inhibitory Mechanism of Embryonic Ectoderm Development Subunit by Triazolopyrimidine Derivatives as Inhibitors through Molecular Dynamics Simulation.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Molecular Dynamics Simulation* ; Ectoderm*/metabolism; Polycomb Repressive Complex 2/chemistry ; Polycomb Repressive Complex 2/metabolism

Inhibition of the Embryonic Ectoderm Development (EED) subunit in Polycomb Repressive Complex 2 (PRC2) can inhibit tumor growth. In this paper, we selected six experimentally designed EED competitive Inhibitors of the triazolopyrimidine derivatives class. We investigated the difference in the binding mode of the natural substrate to the Inhibitors and the effects of differences in the parent nuclei, heads, and tails of the Inhibitors on the inhibitory capacity. The results showed that the binding free energy of this class of Inhibitors was close to or lower compared to the natural substrate, providing an energetic basis for competitive inhibition. For the Inhibitors, the presence of a strong negatively charged group at the 6-position of the parent nucleus or the 8'-position of the head would make the hydrogen atom on the head imino group prone to flip, resulting in the vertical movement of the parent nucleus, which significantly decreased the inhibitory ability. When the 6-position of the parent nucleus was a nonpolar group, the parent nucleus would move horizontally, slightly decreasing the inhibitory ability. When the 8'-position of the head was methylene, it formed an intramolecular hydrophobic interaction with the benzene ring on the tail, resulting in a significant increase in inhibition ability.

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20220508114RC Jilin Provincial Science and Technology Development Plan; 2022171, 2023CX184 Jilin University Graduate Innovation Research Program Project; KJLT202312 Jilin Provincial Association for Science and Technology Domestic and Foreign Academic Exchange Project; JGJX2022D31 Jilin Province Higher Education Research Project; 2022Q3 Jilin Provincial Social Science Foundation; 2022JGZ032 Jilin University Graduate Teaching Reform Project

Keywords: EED; MM/PBSA; inhibitory mechanism; molecular dynamics simulation; triazolopyrimidine derivatives

EC 2.1.1.43 (Polycomb Repressive Complex 2)

Date Created: 20231223 Date Completed: 20231225 Latest Revision: 20231225

20231225

PMC10745707

10.3390/molecules28247997

38138487