Pharmacophore Subject

Compounds and their conformational models were imported to Catalyst and subjected to the HypoGen routine to build chemical feature-based pharmacophore models using hydrogen bond acceptor lipid (HBA), hydrogen bond donor (HBD), positive ionizable (PI), ring aromatic (RA) and hydrophobic ... 

Do I like the proposed hypothesis Although very subjective, this approach tends to counter-balance the inherent imperfections of automated methods. Programs such as DISCO and HipHop will provide multiple output models among which the expert has to choose the most acceptable. The eye is often the first and best critic for the pharmacophore hypotheses. 

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... 

The seven compounds were first subjected to an exhaustive conformational search utilizing the Monte Carlo (MC) Multiple Minimum algorithm as available in MacroModel. The resulting conformers were then clustered using distances between the potential pharmacophore features. A minimum energy conformation in each of the clusters was used as input to DISCO algorithm. DISCO models were visually inspected and one of them was used as a 3-D query in the... 

This section is not intended to provide an in-depth gnide to the development of pharmacophore models, bnt we hope that the benefit of including this type of analysis is self-evident. There are many excellent guides and pnblications on this subject available in the literature [11-13]. The basic steps performed for pharmacophore development are as follows ... 

In addition to their use in the in situ induction of conformational transitions, switch-peptides (O-acyl isopeptides) may serve as alternative solubilizing technique in peptide synthesis [207-214]. The elaboration of these concepts, notably the rational design of dynamic pharmacophores as new type of therapeutically useful compounds, is the subject of our current research. 

The main difficulty for commonly used 3D descriptors results from the treatment of conformational flexibility. Considering that only a single conformation is inadequate for most classes of pharmaceutically relevant molecules, averaging over conformational space provides only a very rough view as to what is intended to be described, namely the possible arrangement of pharmacophoric groups in Cartesian space. In this section a more detailed view on three subjectively selected approaches to describe molecular similarity will be presented. The approaches have in common the fact that similarity is quantified to a less dependable degree from only the 2D structure or specific 3D conformations. 

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