Structure-based pharmacophore modeling

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 

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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... 

Critical Remarks Regarding Structure-based Pharmacophore Models... 

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

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... 

TABLE 10.1 Target Proteins Used for Structure-Based Pharmacophore Modeling... 

For each of the selected target proteins, a set of 10 pharmacophore models was generated based on receptor-inhibitor complexes from the PDB. The three allosteric sites of hepatitis C virus (HCV) polymerase were represented by three, five, and two models, respectively. Structure-based pharmacophore model generation was performed with the software LIGANDSCOUT using the default settings and... 

Steindl, T. M., Schuster, D., Wolber, G., Laggner, C., Langer, T. High-throughput structure-based pharmacophore modelling as a basis for successful parallel virtual screening. J. Comput.-Aided Mol. Des. 2006, 20, 703-715. 

Structure-Based Pharmacophore Model for Selective COX-2 Inhibitors... 

Figure 12.6 Example for successful structure-based virtual screening to identify submicromolar tRNA-guanine transglycosylase (TGT) inhibitors based on X-ray structures of weaker ligands, (a) X-ray structure of Zymomonas mobilis TGT at 2.1 A resolution (PDB entry 1N2V). (b) Experimental binding mode for pyridazinedione scaffold (K 83 pM) including structural water molecules from 1N2V. (c) Definition of structure-based pharmacophore model with ligand interactions...

Figure 15.4 Structure-based pharmacophore model derived from allantodapsone docked to the PRMTl substrate binding pocket. The individual features are annotated.

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