Document Report Card

ID: ALA1140428

Journal: J Med Chem

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

Authors: Costanzi S, Joshi BV, Maddileti S, Mamedova L, Gonzalez-Moa MJ, Marquez VE, Harden TK, Jacobson KA.

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.

CiteXplore: 16366591

DOI: 10.1021/jm050911p