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人P2Y(6)受体：分子建模基于独特的构象偏好实现了新型激动剂的合理设计。

Human P2Y(6) receptor: molecular modeling leads to the rational design of a novel agonist based on a unique conformational preference.

作者信息

Costanzi Stefano, Joshi Bhalchandra V, Maddileti Savitri, Mamedova Liaman, Gonzalez-Moa Maria J, Marquez Victor E, Harden T Kendall, Jacobson Kenneth A

机构信息

NIDDK, National Institutes of Health, DHHS, Bethesda, Maryland 20892. USA.

出版信息

J Med Chem. 2005 Dec 29;48(26):8108-11. doi: 10.1021/jm050911p.

DOI:10.1021/jm050911p
PMID:16366591
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2583457/
Abstract

Combining molecular dynamics (MD) in a hydrated phospholipid (DOPC) bilayer, a Monte Carlo search, and synthesis of locked nucleotide analogues, we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y(6) receptor. 2'-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than that for the corresponding flexible 2'-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.

摘要

结合水合磷脂（二油酰磷脂酰胆碱，DOPC）双层中的分子动力学（MD）、蒙特卡罗搜索以及锁定核苷酸类似物的合成，我们发现核糖的Southern构象对于P2Y(6)受体识别配体而言是更优的。2'-脱氧-(S)-甲氧基碳环尿苷二磷酸被发现是该受体的完全激动剂，其效力比相应的柔性2'-脱氧尿苷二磷酸高10倍。分子动力学结果还表明，激动剂结合后第二细胞外环会发生构象变化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/2a3d485058a6/nihms64826f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/22094b96c499/nihms64826f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/7c79612dad7e/nihms64826f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/9131d03ab1e0/nihms64826f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/2a3d485058a6/nihms64826f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/22094b96c499/nihms64826f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/7c79612dad7e/nihms64826f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/9131d03ab1e0/nihms64826f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0170/2583457/2a3d485058a6/nihms64826f4.jpg

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