SHOP: Receptor-Based Scaffold HOPping by GRID-Based Similarity Searches

被引：14

作者：

Bergmann, Rikke ^{[1
]}

Liljefors, Tommy ^{[1
]}

Sorensen, Morten D. ^{[2
]}

Zamora, Ismael ^{[3
,4
]}

机构：

[1] Univ Copenhagen, Fac Pharmaceut Sci, Dept Med Chem, DK-2100 Copenhagen, Denmark

[2] LEO Pharma AS, DK-2750 Ballerup, Denmark

[3] Lead Mol Design, Barcelona 08172, Spain

[4] IMIM Univ Pompeu Fabra, Grp Recerca Biomed, Barcelona 08124, Spain

来源：

JOURNAL OF CHEMICAL INFORMATION AND MODELING | 2009年 / 49卷 / 03期

关键词：

P38 MAP KINASE; CYCLIN-DEPENDENT KINASE; DE-NOVO DESIGN; INDEPENDENT DESCRIPTORS; CRYSTAL-STRUCTURES; ACCURATE DOCKING; TYROSINE KINASE; BINDING-SITES; INHIBITORS; IDENTIFICATION;

D O I：

10.1021/ci800391v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new field-derived 3D method for receptor-based scaffold hopping, implemented in the software SHOP, is presented. Information from a protein-ligand complex is utilized to substitute a fragment of the ligand with another fragment from a database of synthetically accessible scaffolds. A GRID-based interaction profile of the receptor and geometrical descriptions of a ligand scaffold are used to obtain new scaffolds with different structural features and are able to replace the original scaffold in the protein-ligand complex. An enrichment study was successfully performed verifying the ability of SHOP to find known active CDK2 scaffolds in a database. Additionally, SHOP was used for suggesting new inhibitors of p38 MAP kinase. Four p38 complexes were used to perform six scaffold searches. Several new scaffolds were suggested, and the resulting compounds were successfully docked into the query proteins.

引用

页码：658 / 669

页数：12

共 56 条

[1] The Compressed Feature Matrix - a novel descriptor for adaptive similarity search [J].