A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for ligands and proteins (FLAP): Theory and application
A common reference framework for analyzing/comparing proteins and ligands. Fingerprints for ligands and proteins (FLAP): Theory and application
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DOI：
10.1021/ci600253e
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发表时间：
2007-03-01
影响因子：
5.6
通讯作者：
Mason, Jonathan S.
中科院分区：
文献类型：
--
作者：
Baroni, Massimo;Cruciani, Gabriele;Mason, Jonathan S.
详细描述了一种快速的新算法(配体和蛋白质或翻盖的指纹)，该算法能够使用四点药效团指纹和分子空腔形状的公共参考框架来描述小分子和蛋白质结构。该程序首先使用格子力场来计算分子相互作用场，然后使用这些相互作用场来确定特定的目标位置，在这些位置上，具有小分子特征的高能相互作用将非常有利。这样计算出的靶点然后被Flap用来建立存在于给定靶点的所有可能的四点药效团。一种相关的方法可以应用于小分子，直接使用晶格原子类型来识别药效特征，这种对目标和配体的互补描述随后导致了几种新的应用。Flip可用于选择性研究或相似性分析，以便比较大分子，而不是将它们重叠。可以比较蛋白质家族并将其归类为目标类别，而不需要从先前的知识中产生偏见，也不需要蛋白质叠加、比对或基于知识的比较。通过对药效团的分子识别，FLAP可以有效地用于基于配体的虚拟筛选和基于结构的虚拟筛选。最后，新方法可以计算化学计量学分析的描述符，并可以启动对接过程。本文件介绍了新程序的背景，并包括说明新方法的几个相关应用的案例研究。
A fast new algorithm (Fingerprints for Ligands And Proteins or FLAP) able to describe small molecules and protein structures using a common reference framework of four-point pharmacophore fingerprints and a molecular-cavity shape is described in detail. The procedure starts by using the GRID force field to calculate molecular interaction fields, which are then used to identify particular target locations where an energetic interaction with small molecular features would be very favorable. The target points thus calculated are then used by FLAP to build all possible four-point pharmacophores present in the given target site. A related approach can be applied to small molecules, using directly the GRID atom types to identify pharmacophoric features, and this complementary description of the target and ligand then leads to several novel applications. FLAP can be used for selectivity studies or similarity analyses in order to compare macromolecules without superposing them. Protein families can be compared and clustered into target classes, without bias from previous knowledge and without requiring protein superposition, alignment, or knowledge-based comparison. FLAP can be used effectively for ligand-based virtual screening and structure-based virtual screening, with the pharmacophore molecular recognition. Finally, the new method can calculate descriptors for chemometric analysis and can initiate a docking procedure. This paper presents the background to the new procedure and includes case studies illustrating several relevant applications of the new approach.