22.pharmacophore

pharmacophore

1. Pharmachophore
Identification of pharmachophore
Abhijeet Kadam
TSEC
BioTechnology

2. Defination
●A pharmacophore is a specific 3D arrangement
of functional groups within a molecular
framework that are necessory to bind to a
macromolecule and/or an enzyme active site
●The identification of pharmacophore is
important step in understanding the interactions
between a receptor and a ligand

3. Pharmacophore
●Many possible iterations between ligand and receptor
●Depending on size of active, various steric-
electrostatic and hydrophobic contacts
●Some contacts or sites are more important than
others
●The specific interactions that are crucial for ligand
recognition and binding by the receptor are thermal
pharmacophore
●These interactions are directly involved in the
structural integrity of receptor or in the mechanism of
its action

4. Pharmacophore
●Pharmacophore model is derived from a set of
known ligands for a target
●Aslo using the set of features common to a
series of active molecules
●Features may include – acceptors, donors, ring
centroids, hydrophobes etc
●A 3D pharmacophore is used to define
relationships between groups or features

5. Pharmacophore
●Pharmacophore hypothisis are generated by the
multiple conformations of the set of molecules
●When protein is unknown, it is more efficient
●With the generated hypothysis, it is possible to
search the database for new hit compounds
●Searching the possible low energy conformations
of known inhibitors can identify pharmacophores

6. Different methods
●The conformation search can be quite large
and can be approaches using folowing methods
–Systematic search method
–Distance geometry method
–Clique detection algorithm

7. Systematic search method
●Generates sterically allowed molecular
conformations by systematically varying sets of
specified torsion angles
●Www.accelrys.com/cerius2/conformers.html

8. Distance geometry method
●Randomly samples conformations and are
particularly powerful for problems dealing with
molecular matching and flexibility
●Used by rubicon
●Www.daylight.com/products/rubicon.html

9. Clique detection algorithm
●Searhes common sets of inter feature distances
within the group of active molecules
●Tolerences on the distances matches aaccount
for the use of discret conformations and
uncertenties in pharmacophore
●Used by DiscoTech
●Www.tripos.com/scitech/insilicodisc/PharmaPer
ception/DiscoTech.html

10. Clique detection algorithm
●Searhes common sets of inter feature distances
within the group of active molecules
●Tolerences on the distances matches aaccount
for the use of discret conformations and
uncertenties in pharmacophore
●Used by DiscoTech
●Www.tripos.com/scitech/insilicodisc/PharmaPer
ception/DiscoTech.html