Identifying Interactions that Determine Fragment Binding at Protein Hotspots

被引:72
作者
Radoux, Chris J. [1 ,4 ]
Olsson, Tjelvar S. G. [1 ,2 ]
Pitt, Will R. [3 ]
Groom, Colin R. [1 ]
Blundell, Tom L. [4 ]
机构
[1] Cambridge Crystallog Data Ctr, 12 Union Rd, Cambridge CB2 1EZ, England
[2] John Innes Ctr, Norwich Res Pk,Colney Lane, Norwich NR4 7UH, Norfolk, England
[3] UCB, 208 Bath Rd, Slough SL1 3WE, Berks, England
[4] Univ Cambridge, Dept Biochem, Sanger Bldg,80 Tennis Court Rd, Cambridge CB2 1GA, England
基金
英国生物技术与生命科学研究理事会;
关键词
DRUGGABLE HOT-SPOTS; LIGAND-BINDING; CRYSTAL-STRUCTURES; GROUP EFFICIENCY; DRUG DISCOVERY; SITES; HYDRATION; LEADS; THERMODYNAMICS; IDENTIFICATION;
D O I
10.1021/acs.jmedchem.5b01980
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Locating a ligand-binding site is an important first step in structure-guided drug discovery, but current methods do little to suggest which interactions within a pocket are the most important for binding. Here we illustrate a method that samples atomic hotspots with simple molecular probes to produce fragment hotspot maps. These maps specifically highlight fragment-binding sites and their corresponding pharmacophores. For ligand-bound structures, they provide an intuitive visual guide within the binding site, directing medicinal chemists where to grow the molecule and alerting them to suboptimal interactions within the original hit. The fragment hotspot map calculation is validated using experimental binding positions of 21 fragments and subsequent lead molecules. The ligands are found in high scoring areas of the fragment hotspot maps, with fragment atoms having a median percentage rank of 97%. Protein kinase B and pantothenate synthetase are examined in detail. In each case, the fragment hotspot maps are able to rationalize a Free Wilson analysis of SAR data from a fragment-based drug design project.
引用
收藏
页码:4314 / 4325
页数:12
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