Pharmacophore identification and novel drug design
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pharmacophore is a part of a molecular structure that is responsible for a particular biological or pharmacological interaction that it undergoes. This identification leads to the development of designing a new drug.
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Pharmacophore identification and novel drug design
- 1. Pharmacophore identification and novel drug design. BY BENITTA BENNY MSc BIOINFORMATICS
- 2. What is pharmacophore? • The pharmacophore is the group of these properties that form a vital part of a drug . • An ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response". • A pharmacophore model explains how structurally diverse ligands can bind to a common receptor site. • Pharmacophore models can be used to identify through de novo design or virtual screening novel ligands that will bind to the same receptor.
- 3. Pharmacophore -Features • Typical pharmacophore features include hydrophobic centroids, aromatic rings, hydrogen bond acceptors or donors, cations, and anions. These pharmacophoric points may be located on the ligand itself or may be projected points presumed to be located in the receptor. • The features need to match different chemical groups with similar properties, in order to identify novel ligands. Ligand-receptor interactions are typically “polar positive”, “polar negative” or “hydrophobic”. A well-defined pharmacophore model includes both hydrophobic volumes and hydrogen bond vectors.
- 4. Process for developing a pharmacophore model They generally involves the following steps: • Select a training set of ligands – Choose a structurally diverse set of molecules that will be used for developing the pharmacophore model. As a pharmacophore model should be able to discriminate between molecules with and without bioactivity, the set of molecules should include both active and inactive compounds. • Conformational analysis – Generate a set of low energy conformations that is likely to contain the bioactive conformation for each of the selected molecules. • Molecular superimposition – Superimpose ("fit") all combinations of the low-energy conformations of the molecules. Similar (bioisosteric) functional groups common to all molecules in the set might be fitted (e.g., phenyl rings or carboxylic acid groups). The set of conformations (one conformation from each active molecule) that results in the best fit is presumed to be the active conformation. • Abstraction – Transform the superimposed molecules into an abstract representation. For example, superimposed phenyl rings might be referred to more conceptually as an 'aromatic ring' pharmacophore element. Likewise, hydroxy groups could be designated as a 'hydrogen-bond donor/acceptor' pharmacophore element. • Validation – A pharmacophore model is a hypothesis accounting for the observed biological activities of a set of molecules that bind to a common biological target. The model is only valid insofar as it is able to account for differences in biological activity of a range of molecules.
- 5. Applications • In modern computational chemistry, pharmacophores are used to define the essential features of one or more molecules with the same biological activity. • A database of diverse chemical compounds can then be searched for more molecules which share the same features arranged in the same relative orientation. • Pharmacophores are also used as the starting point for developing 3D-QSAR models. Such tools and a related concept of "privileged structures", which are "defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications" aid in drug discovery.
- 6. Pharmacophore in Drug Design and Discovery • A pharmacophore model is a geometrical description of the chemical functionalities required of a ligand to interact with the receptor. modern medicinal chemistry is to reduce the overall cost - discovery and development of a new drug, by identifying the most promising candidates to focus on the experimental efforts. • Experimental screening for lead structure determination suffers from limitation with respect to the possible number of compounds that can be submitted to a high-throughput bio-assay and with the low number of hits obtained that is in the range of 0.1%. • The pharmacophore approach has proven to be successful, allowing (i) the perception and understanding of key interactions between a target and a ligand and (ii) the enrichment of hit rates obtained in experimental screening of subsets that have been obtained from in silico screening experiments. • Pharmacophore mapping is one of the major elements of drug design in the absence of structural data of the target receptor.it can be used as queries for retrieving potential leads from structural databases (lead discovery), for designing molecules with specific desired attributes (lead optimization), and for assessing similarity and diversity of molecules using pharmacophore fingerprints. • It can also be used to align molecules based on the 3D arrangement of chemical features or to develop predictive 3D QSAR models.
- 7. THANK YOU