Structure-based pharmacophore

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. 

J., Zheng, W. (2008) Novel approach to structure-based pharmacophore search using computational geometry and shape matching techniques. / Chem Inf Model 48, 889-901. 

In this chapter, we describe the results of our studies we aimed at the development of a general computational procedure to generate automatically and unbiased objective pharmacophore models using the GRID approach and starting with PDB macromolecular complexes. Within the context of structure-based pharmacophore modeling, it represents an approach that is somehow complementary to that described in Chapter 6. We have used logically combined maps... 

Fig. 8.9 Composite protein structure-based pharmacophore used for virtual screening. Donor features and their corresponding interaction partners in the protein are colored blue, acceptor features and their correspond ing interaction partners are colored red and the acceptor/donor feature and the corre-...

Critical Remarks Regarding Structure-based Pharmacophore Models... 

Example of a structure-based pharmacophore model (Brenk et al., 2003)... 

The structure-based pharmacophore was built using the crystallographic coordinates of argatroban complexed with thrombin [101] and the functional group definitions contained within the CATALYST software to predict the effects on the K[ values of structural modification of a set of homologous 4-aminopyridine (4-AP) thrombin inhibitors. 

Finally, dynamic structure-based pharmacophore models can be derived through a method first described by Carlson et al that uses multiple conformations of the target protein, which are obtained either by molecular dynamics simulation or by the use of multiple experimentally determined conformations. The binding sites of the respective snapshots are flooded with small molecular probes (e.g., methanol for hydrogen-bond interactions and benzene for aromatic hydrophobic interactions) and while the protein structure is held rigid the probe molecules are subjected to a low-temperature Monte Carlo minimization where they undergo multiple, simultaneous gas-phase... 

In structure-based pharmacophore modeling, excluded volume spheres can be placed at atoms forming the binding site, a feature that has also been included in LigandScout. For faster screening and less restrictive models, LigandScout alternatively allows for the placement of only a few excluded volume spheres at the lipophilic side-chain residues that are in contact with hydrophobic features in the ligand. We have found that excluded volume... 

The pharmacophore-based screening approach has recently been shown to be also very successful for the identification of bio-active natural products. Rollinger et derived a structure-based pharmacophore model on the... 

Finally, while pharmacophore and docking methods are still two distinct methods for VS, the distance between them appears to be growing smaller structure-based pharmacophore methods are trying to include more and more information about the binding site (Sections 3.4.2 and 3.4.3), while some docking programs have successfully incorporated pharmacophore constraints, which we discuss in the next section. 

Computational search in chemical databases for compounds that potentially satisfy the key interactions, fit into the binding site, and form additional interactions with the protein this is done by means of docking and/or structure-based pharmacophore searches. 

In the final round, the authors reported the development of a structure-based pharmacophore that was also used for To achieve this goal, a homology... 

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