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Pharmacophore modeling
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A pharmacophore model is a collection of pharmacophore elements and a pharmacophore element is defined as an atom or functional group (a collection of atoms) essential for biological activity. In other words a pharmacophore model is a model of the interaction between a protein and its ligands derrived using structural information of the ligands.
First step in the construction of the model is to find a set of structurally diverse high affinity ligands. It is important that the scaffold of the ligands are structurally diverse, where as diversity of the substituents can often be used to define regions of protein subtype selectivity. (The ligand could be regarded as a christmas tree where the scaffold corresponds to the steem and branches where as all the christmas decoration corresponds to the substituents) Next step is to perform a conformational analysis on each ligand. Third step is to superimpose conformations of different ligands and find the one where the pharmacophore elements overlay. Finally the model can be defined as the 3D position of the pharmacophore elements.
A pharmacophore model has several applications. A tool for better understanding observed binding data; the design of new ligands with higher affinity for the protein of interest, better selectivity or some other improved physical or chemical properties; ligand based virtuel screening. For the last mentioned application the model itself, the shape of one or several molecules fitted to the model or a combination of the two can be used as a query for searching 3D conformational databases.
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This example show a pharmacophore model for neurokinin antagonists. The model consists of 3 aromatic or hydrophobic groups, a hydrogen bond donor and 2 hydrogen bond acceptors.
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Links
Molecular Mechanics (MM)
Pharmacophore Modeling
Docking
Protein Modeling
Molecular Quantum Mechanics
Physical & Chemical properties
Ph.D. Project
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