Pharmacophore identification
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Transcript of Pharmacophore identification
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S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician
Drug Design
Pharmacophore IdentificationPharmacophore Identification
S.Prasanth Kumar, S.Prasanth Kumar, BioinformaticianBioinformatician
S.Prasanth Kumar Dept. of Bioinformatics Applied Botany Centre (ABC) Gujarat University, Ahmedabad, INDIA
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Pharmacophore
A pharmacophore that indicates the key features of a series of active molecules
In drug design, the term 'pharmacophore‘ refers to a set of features that is common to a series of active molecules
Hydrogen-bond donors and acceptors, positively and negatively charged groups, and hydrophobic regions are typical features
We will refer to such features as 'pharmacophoric groups'
H HBD HBA R
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Bioisosteres
Bioisosteres, which are atoms, functional groups or molecules with similar physical and chemical properties such that they produce generally similar biological properties
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3D-Pharmacophores
A three-dimensional pharmacophore specifies the spatial relation- ships between the groups
Expressed as distance ranges,angles and planes
A commonly used 3D pharmacophore for antihistamines contains two aromatic rings and a tertiary nitrogen
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Constrained Systematic Search
Deduce which features are required for activity
Angiotension-converting enzyme (ACE), which is involved in regulating blood pressure
Four typical ACE inhibitors Captopril
Interacts with an Arg residue of enzyme
a zinc-binding group
H bonds to a hydrogen-bond donor in enzyme
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Constrained Systematic Search
Systematic search over all molecules
Combinatorial explosionNo systematic conformational analysis
Considered
Reduces torsion angles of the rotatable bonds = reduced conformational space
Conformational space Not Explored
Systematic search over 20-30 molecules
Combinatorial explosion associated with a systematic conformational analysis
Exhaustiveness Systematic search
Choose the most conformationally restricted molecules first
Selection
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Constrained Systematic Search
Evaluated distance for 1st molecule
Permitted distances for 1st and 2nd molecule
4 points 5 distances
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Ensemble Distance Geometry
Used to simultaneously derive a set of conformations with a previously defined set of pharmacophoric groups overlaid
Special Feature : conformational spaces of all the molecules are considered simultaneously
Nicotinic agonists (Previously defined sets: A,B and C)
N1= no. of atoms in molecule 1
N2= no. of atoms in molecule 2
N3= no. of atoms in molecule 3
N4= no. of atoms in molecule 4
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Ensemble Distance Geometry
Distance matrix construction
Dimensions = sum of the atoms in all the molecules.
Specify lower and upper bounds
Lower bounds for atoms that are in different molecules = zeromolecules can be overlaid in 3D spaceUpper bounds for pairs of atoms that are in different molecules = large value Required to be superimposed in the pharmacophore
repeat
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Ensemble Distance Geometry
A B C
Note: these are not pharmacophore features but pharmacophoric sets
A A BB C C
LB : 4.8 ˚A
UB : 5.1 ˚A
LB : 4.0 ˚A
UB : 4.3 ˚A
1.2 ˚A
No Bounds here
Remove distorted geometries
A
B
C
4.8 +/- 0.3 ˚A1.2 ˚A
4.0 +/- 0.3 ˚A
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Clique Detection Methods
When many pharmacophoric groups are present in the molecule it may be very difficult to identify all possible combinations of the functional groups
Clique is defined as a 'maximal completely connected subgraph'
Clique detection algorithms can be applied to a set of pre-calculated conformations of the molecules
Cliques are based upon the graph-theoretical approach to molecular structure
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Clique Detection Methods
Graph G
G is not a completely connected graph, because there is not an edge between all the nodes.
subgraph S1 is not a completely connected subgraph, because there is no edge between nodes 1 and 8
S2 is a completely connected sub-graph
S2 is not a clique, because it is not a maximal completely connected subgraph;
S2 can be converted into a clique C1 by adding node 8
Another clique C2
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Clique Detection Methods
Find similar pattern
cliques O1(A) O2(B)
O2(A) O1(B)
H(A) H2(B)
O1(A) O1(B)
O2(A) O2(B)
H(A) H3(B) NEWLY ADDED NODE
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Thank You For Your Attention !!!