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

Bioisosteres

Bioisosteres, which are atoms, functional groups or molecules with similar physical and chemical properties such that they produce generally similar biological properties

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

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

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

Constrained Systematic Search

Evaluated distance for 1st molecule

Permitted distances for 1st and 2nd molecule

4 points 5 distances

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

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

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

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

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

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

Thank You For Your Attention !!!