Another Brick in the Wall. Validation of the 蟽1 Receptor 3D Model by Computer-Assisted Design, Synthesis, and Activity of New 蟽1 Ligands

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• 作者：Erik Laurini ; Domenico Marson ; Valentina Dal Col ; Maurizio Fermeglia ; Maria Grazia Mamolo ; Daniele Zampieri ; Luciano Vio ; Sabrina Pricl
• 刊名：Molecular Pharmaceutics
• 出版年：2012
• 出版时间：November 5, 2012
• 年：2012
• 卷：9
• 期：11
• 页码：3107-3126
• 全文大小：711K
• 年卷期：v.9,no.11(November 5, 2012)
• ISSN：1543-8392

文摘

Originally considered an enigmatic polypeptide, the 蟽₁ receptor has recently been identified as a unique ligand-regulated protein. Many studies have shown the potential of 蟽₁ receptor ligands for the treatment of various diseases of the central nervous system (CNS); nevertheless, almost no information about the 3D structure of the receptor and/or the possible modes of interaction of the 蟽₁ protein with its ligands have been unveiled so far. With the present work we validated our 蟽₁ 3D homology model and assessed its reliability as a platform for 蟽₁ ligand structure-based drug design. To this purpose, the 3D 蟽₁ model was exploited in the design of 33 new 蟽₁ ligands and in their ranking for receptor affinity by extensive molecular dynamics simulation-based free energy calculations. Also, the main interactions involved in receptor/ligand binding were analyzed by applying a per residue free energy deconvolution and in silico alanine scanning mutagenesis calculations. Subsequently, all compounds were synthesized in our laboratory and tested for 蟽₁ binding activity in vitro. The agreement between in silico and in vitro results confirms the reliability of the proposed 蟽₁ 3D model in the a priori prediction of the affinity of new 蟽₁ ligands. Moreover, it also supports and corroborates the currently available biochemical data concerning the 蟽₁ protein residues considered essential for 蟽₁ ligand binding and activity.

Keywords:

cs.org/action/doSearch?action=search&searchText=%CF%831+receptor&qsSearchArea=searchText">蟽₁ receptor; cs.org/action/doSearch?action=search&searchText=homology+model&qsSearchArea=searchText">homology model; cs.org/action/doSearch?action=search&searchText=pharmacophore+model&qsSearchArea=searchText">pharmacophore model; cs.org/action/doSearch?action=search&searchText=MM%2FPBSA&qsSearchArea=searchText">MM/PBSA; cs.org/action/doSearch?action=search&searchText=per%5C-residue+free+energy+decomposition&qsSearchArea=searchText">per-residue free energy decomposition; cs.org/action/doSearch?action=search&searchText=computational+alanine+scanning&qsSearchArea=searchText">computational alanine scanning