MDMX公司
化学
藤黄酸
平方毫米
生物物理学
体内
分子动力学
小分子
生物化学
立体化学
体外
生物
基因
计算化学
遗传学
作者
Aisha I. El habbash,Ahmed A. El‐Rashedy,Mahmoud E. S. Soliman
标识
DOI:10.2174/0929867329666220610194919
摘要
Background: Mouse Double Minute 2 Homolog (MDM2) oncogenic protein is the principal cellular antagonist of the p53 tumor suppressor gene. Restoration of p53 activity by inhibiting the MDM2-P53 interactions at the molecular level has become the cornerstone of cancer research due to its promising anticancer effects. Natural medicinal products possess various chemical structures and represent an essential source for drug discovery. α-Mangostin (AM) and gambogic acid (G250) are plant-derived compounds that showed inhibitory effects on MDM2-P53 interactions in-vitro and in-vivo. Methods: Despite the many clinical studies which performed deeper insight about the molecular understanding of the structural mechanisms exhibited by α-Mangostin and Gambogic acid-binding to MDM2 remains critical. In this study, comparative molecular dynamics simulations were performed for each Apo and bound p53 and MDM2 proteins to shed light on the MDM2-p53 interactions and get a better understanding of the inhibition mechanisms. Results: Results revealed atomistic interaction of AM and G250 within the MDM2-p53 interaction cleft. Both compounds mediate the interaction between the α-helix motifs of the p53 amino-terminal domain. Which caused a significant separation between orthogonally opposed residues, specifically Lys8 and Gly47 residues of the p53 and MDM2, respectively. Contrasting changes in magnitudes were observed in per-residue fluctuation on AM and G250 (~0.04 nm and ~2.3 nm, respectively). The Radius of gyration (~0.03 nm and 0.04 nm, respectively), C-alpha deviations (~0.06 nm and 0.1 nm, respectively). The phenolic group of AM was found to establish hydrogen interactions with Glu28 and His96 residues of MDM2. The trioxahexacyclo-ring of G250 also forms hydrogen bond interactions with Lys51 and Leu26 residues of MDM2. Conclusion: Utilizing the information provided on the inhibitory binding mode adopted by each compound in this study may further assist in the tailored designs for cancer therapeutics.
科研通智能强力驱动
Strongly Powered by AbleSci AI