Drugs pharmacophore

Pharmacophoric patterns have been proposed as the result of structure-activity studies, modeling studies, mechanistic studies, and enzyme structural studies. While two atom ("distance") and three atom ("triangle") pharmacophoric patterns have been proposed, we would not expect these to be as discriminating as more detailed patterns. Proposed pharmacophoric patterns have been reviewed by Kler,9 Korolkovas,10 and Gund.7 Some additional proposed patterns of drug pharmacophores and of complementary receptor maps are listed in Table I. 

Figure 1 Screen from MACCS-3D displaying a hit retrieved from the MDL Drug Data Repoit (MDDR-3D) database based on a centra) nervous system active drugs pharmacophore from Ref. 9f. Query is overlaid on the hit to show how it fits to the query constraints...

Guner O F (Editor) 2000. Pharmacophore Perception, Development, and Use in Drug Design. International University Line Biotechnology Series, 2. 

Since the summation in Eq. (12) may be on any subset of atoms, it can be fine-tuned to best suit the problem at hand. The summation may be over the whole molecule, but it is very common to calculate conformational distances based only on non-hydrogen heavy atoms or, in the case of proteins, even based on only the backbone Ca atoms. Alternatively, in a study related to drug design one may consider, for example, focusing only on atoms that make up the pharmacophore region or that are otherwise known to be functionally important. 

Pharmacophore. The portion of the drug molecule that is responsible for the biologic activity of the drug. 

The five-membered heterocycles discussed in the preceding chapter more often than not constituted the pharmacophoric moieties of the drugs in question. Drugs based on six-... 

Today, 3D databases, which provide the means for storing and searching for 3D information of compounds, are proven to be useful tools in drug discovery programs. This is well exemplified with the recent discovery of novel nonpeptide HIV-1 protease inhibitors using pharmacophore searches of the National Cancer Institute 3D structural database [13-15]. 

This method represents the most common and traditional application of computational tools to rational drug design. From a list of molecules of known activity, one can establish a 3D-pharmacophore hypothesis that is then transformed into a 3D-search query. This query is then used to search a 3D database for structures that fit the hypothesis within a certain tolerance. If the yield of active molecules is significant, then the query can be used to predict activities on novel compounds. In our situation, the enantiophore is built from the superposition of a list of sample molecules, which are all well separated on a given CSR Hence, the common features of this series of molecules can become a good enantiophore hypothesis for the enantiores-olution on this CSR... 

However, most natural peptides are composed of L-form a-amino acids and because of the ubiquitous prevalence of peptidases they have limited biostability, and consequently low bioavailability. Thus, a novel field of peptidomimetics has emerged in drug discovery, in attempts to design non-peptide compounds mimicking the pharmacophore and thus the activity of the original peptide. 

Davies K. Using pharmacophore diversity to select molecules to test from commercial catalogues. In Chaiken IM and Janda KD, editors. Molecular diversity and combinatorial chemistry. Libraries and drug discovery. Washington DC American Chemical Society, 1996 309-16. 

Guner OF. Preface. In Guner OF, editor, Pharmacophore perception, development, and use in drug design. La Jolla International University Line, 2000. 

Beno BR, Mason JS. The design of combinatorial libraries using properties and 3D pharmacophore fingerprints. Drug Discov Today 2001 6(5) 251-8. 

Ekins S, De Groot MJ, Jones JP. Pharmacophore and three-dimensional quantitative structure activity relationship methods for modeling cytochrome P450 active sites. Drug Metab Dispos 2001 29 936-44. 

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