Pharmacophore structure-based pharmacophores

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Varady J, Wu X, Fang X, Min J, Hu Z, Levant B, Wang S. Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor discovery of novel and potent D3 ligands through a hybrid pharmacophore-and structure-based database searching approach. / Med Chem 2003 46 4377-92. 

Brenk R, Meyer EA, Reuter K, Stubbs MT, Garcia GA, Diederich E, Klebe G. Crystallographic study of inhibitors of tRNA-guanine transglycosylase snggests a new structure-based pharmacophore for virtual screening. J Mol Biol 2004 338 55-75. 

Keywords VS, Virtual Screening, Lead discovery, lead, HTS, Pharmacophore-Based, Structure-Based, Fragment-based, Ligand-based, Docking, Scoring, hybrid workflows, VS strategy, Benchmarking VS... 

PF1BVS Pharmacophore-based virtual screening SBVS (Protein) Structure-based virtual screening... 

The design of new analogs based on pharmacophore models is complementary to structure-based design. This method may be used even where structural information is available, but is also of use for targets where structural information is not... 

A great variety of methods and techniques are now available for pharmacophore model generation. These methods are based on the appropriate choice of the ligand set (ligand-based, when much information is available on different ligand classes), and/or on one or more target/antitarget proteins (structure-based, particularly useful when... 

Fig. 4.1 Virtual screening tools can be categorized by the compound data to be screened (compound collection, combinatorial library, chemistry space) and the query type (structure-based, ligand-based, descriptor-based, pharmacophore-based). The output is always a list of compounds together with a score quantifying the fit to the query.

The pharmacophore concept has been shown to be of high relevance to virtual screening as a filter in structure-based applications or a stand-alone approach. Input for a pharmacophore can come from different sources a ligand, a ligand series, NMR-derived structure of a related macromolecule, or protein X-ray structure. This information has to be generated, if needed, and productively used for virtual screening. 

Mason, J.S. and Beno, B.R. Library design using BCUT chemistry-space descriptors and multiple four-point pharmacophore fingerprints simultaneous optimization and structure-based diversity. /. Mol. 

Fig. 6. Chemotype enrichment rates using a variety of structure-based virtual screening algorithms and constraint settings for CDK2. DOCK search incorporating target class critical pharmacophore constraints denoted by the mark. Adapted from ref. 70.

Eksterowicz, J. E., Evensen, E., Lemmen, C., et al. (2002) Coupling structure-based design with combinatorial chemistry application of active site derived pharmacophores with informative library design. J. Mol. Graph. Model. 20, 469-477. 

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