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Molecular Similarity and Similarity SearchingSubstructure and 3D pharmacophore searching involve specification of a precise query. In this approach a molecule in the database either matches the query or does not match the query.

In similarity searching the query is typically the entire molecule. A similarity coefficient is calculated and the top scoring molecules from the database are the hits.

If two molecules are found to be similar they are thought to have the same activity.

Similarities are computed based on a set of Molecular Descriptor.

Molecular DescriptorsApart from descriptors that can be calculated from molecular formula or computed 3D structures, experimental data can also be used.

But this is not usually feasible due to unavailability of experimental data and the expenses involved.

Also some molecules mat not have been synthesised yet.

1. Partition Coefficient Most commonly, 1-Octonol Water partition coefficient. Descriptor is Log P , where P Partition Coefficient.Various theoretical methods available for calculation of P.Most widely used are fragment based approaches, in which partition coeff. are calculated as a sum of individual fragment contributions plus correction factors.Widely used program is CLOGP (by Hansch and Leo), employing the above approach.

CLOGP breaks a molecule into fragments by identifying isolating carbons.

These are carbon atoms that are not doubly bonded or triply bonded to a heteroatom.

The carbon atoms and attached hydrogens are considered hydrophobic fragments, with remaining froups of atoms being the polar fragments.Ex; Benzyl bromide & o- methyl acetanilide

One drawback of this method is the need for data for all the fragments in the molecule.

An alternative is to use an atom-based approach in which the molecule is broken down into atom types present. In such a case the partition coeff. is given as a summation of contributions from atoms of each type.

Where, ni is the number of atom type i and ai is the atomic contribution.

2. Molar refractivity

MW is the molecular weight, d is the density and n is the refractive index.

As molecular weight divided by density equals volume, MR gives some indication of the steric bulk of a molecule.

Presence of refractive index term also provides a connection to polarisibility of the molecule.

It can also be calculated using atomic values with some correction factors (Ex; CMR program by Leo and Weininger) 3. Topological indicesKier and Hall have developed a large number of topological indices, that characterizes the molecular structure as a single number.Every non-hydrogen atom in the molecule is characterised by two delta values (the simple delta and the valence delta).

Where, i is the number of sigma electrons for atom i, hi is the number of H atoms bonded to i, ZiV is the number of valence electrons for atom i.Thus this value can differentiate between CH3 from CH2.CH3 has same simple delta value as NH2 but a difference valence delta.

For elements beyond fluorine in the periodic table the valence delta expression is modified as,

where, Zi is the atomic number.

The chi molecular connectivity indices are obtained by summing functions of these delta values. Thus the chi index of zero order (about the atoms) is,

First order chi index involves summation over bonds,

Higher order chi indices involve summations over sequences 2, 3, etc. bonds.

Kappa indices are shape indices of various orders, with first order shape index involving a count over single-bond fragments, second oreder index involving a count of two-bond paths, and so on.

Considering the first order, the extreme shapes are the linear molecule and the graph where every atom is connected to every other atom.

The first order index is given by ,

where, 1P is the number bonds, 1Pmax & 1Pmin are maximum and minimum number of bonds.

The second order shape index is given by,

Kappa-alpha indices are what actually gives info about identity of atoms.

Alpha value is measure of its size relative to some standard,

Alpha value is calculated for molecule by summing individual atomic alphas and then incorporating into shape indices,

This index depends upon the intrinsic state of an atom, which for an atom is given by,

The sum of I and I gives the state of each atom.

These atomic topological states can be combined into a whole-molecule descriptor by calculating the mean square value for the atoms.

A finite number of I values are possible and so a bitstring representation can be obtained by setting the appropriate bit for different I values.4. Pharmacophore KeyDuring conformational analysis, the pharmacophore keys within each conformation are identified.

All possible combinations of three features within each acceptable

conformation are identified together with the distance between them.

Each distance is assigned to a distance bin to get a pharmacophore bit string.

Thus the key codes all possible 3-point pharmacophores that the molecule could express.

These can be used like other binary descriptors.

4- point pharmacophores can also be used but the number of bits is high and hence it is not practical to store them as simple bit strings.

H-bond donor, aromatic ring centroid and basic nitrogen