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Ab Initio QM/MM Study Shows a Highly Dissociated SN2 Hydrolysis Mechanism for the cGMP-Specific Phosphodiesterase-5.

Author: FengLing-Jun, LiZhe, LuoHai-Bin, WuRuibo, WuYinuo

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Overview

This computational study investigated the catalytic hydrolysis mechanism of cGMP by PDE5, a key enzyme in the hydrolysis of the important second messengers cGMP and cAMP. The study found that the reaction proceeds via a SN2 type mechanism with a reaction barrier of 8.88 kcal/mol. The results provide valuable insights for the rational design of more specific inhibitors toward PDE5.
Paper Details　
Original Abstract of the Article :
Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment...See full text at original site
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引用元：
https://doi.org/10.1021/ct500761d

データ提供：米国国立医学図書館（NLM）

Unraveling the Mystery of cGMP-Specific Phosphodiesterase-5 (PDE5)

Phosphodiesterases (PDEs) are enzymes that play a crucial role in regulating cellular signaling pathways. This study delves into the complex world of PDE5, an enzyme specifically responsible for breaking down the signaling molecule cGMP. Think of it like a master craftsman meticulously carving a piece of wood, each cut and stroke revealing the intricate details of the object. The researchers wanted to understand the precise mechanism by which PDE5 breaks down cGMP.

A New Understanding of PDE5's Mechanism

The study used sophisticated computer simulations to unveil the intricate steps involved in the hydrolysis (breakdown) of cGMP by PDE5. They discovered a unique mechanism, unlike previously proposed models, where the transition state is highly dissociated, meaning the bonds are broken and formed in a very specific way. This is like discovering a new technique for wood carving, revealing a hidden beauty and elegance in the process.

Potential for New Drug Development

This study provides a more detailed understanding of PDE5's mechanism, which could have significant implications for drug development. By gaining insights into the intricate workings of this enzyme, researchers can potentially design more specific and effective inhibitors, leading to new therapeutic approaches for various diseases. It's like having a blueprint of the craftsman's tools, allowing us to create better and more precise instruments for healing.

Dr. Camel's Conclusion

This study offers a valuable glimpse into the intricate world of enzyme mechanisms, paving the way for a deeper understanding of cellular processes. By unraveling the mysteries of PDE5, we can pave the path for developing more targeted and effective therapies for a wide range of diseases. It's a reminder that the journey of scientific discovery is filled with unexpected turns and exciting breakthroughs.

Date :
  1. Date Completed 2015-12-22
  2. Date Revised 2015-11-20
Further Info :

Pubmed ID

26583228

DOI: Digital Object Identifier

10.1021/ct500761d

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Languages

English

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