QSAR

QSAR (Quantitative Structure Activity Relation-ship) is a multivariate, mathematical relationship between a set of 1D/2D/3D physicochemical properties (descriptors) and any other property of interest, say biological activity.

Actual Activity log IC50

1. Conformational descriptors
Energy is the energy of the currently selected conformation in the Study Table (it is assumed you have already generated a set of conformations for each model). LowEne is the energy of the most stable conformation in the set of conformations belonging to each molecular model. EPenalty is the difference between Energy and LowEne.

2. Structural descriptors
The available Structural descriptors are, MW Rotlbonds Hbond acceptor Molecular weight Number of rotatable bonds Number of hydrogen bond acceptors

Hbond donor

Number of hydrogen bond donors

There are more than 5 H-bond donors. The molecular weight is over 500. There are more than 10 H-bond acceptors. No. of rings are more than 5. The LogP is over 5.

Poor absorption and permeability are more likely when Lipinskis 5th Rule

3. Electronic descriptors
The following lists of electronic descriptors are available.
Charge Sum of partial charges

Fcharge

Sum of formal charges

Formal Charge = (group number) (non bonding es) (shared es)

Apol
Dipole HOMO LUMO Sr

Sum of atomic polarizabilities

Dipole moment Highest occupied molecular orbital energy Lowest unoccupied molecular orbital energy Superdelocalizability

Sum of atomic polarizabilities (Apol)

Apol computes the sum of the atomic polarizabilities. The polarizabilities are calculated from the coefficients, Ai, used for molecular mechanics calculations:

Pa Ai
i

Polarizability of a molecule is governed by strength with which the nuclear charges control the electrons and prevent their distortion by the applied field.

Dipole moment (Dipole)

It indicates the strength and orientation behavior of a molecule in an electrostatic field. Both the magnitude and the components (X, Y, Z) of the dipole moment are calculated. It is estimated by utilizing partial atomic charges and atomic coordinates.

Dipole properties have been correlated to long-range ligand-receptor recognition and subsequent binding. Pinduced = P=Induced dipolemoment; E=electric field

For example, in the case of chlorobenzenes:

Cl Cl Cl Cl Cl Cl Cl

Highest occupied molecular orbital energy (HOMO) It is the energy (in eV) of the HOMO

- Calculated by the Complete Neglect of Differential Overlap (CNDO/2) method.

It is the highest energy level in the molecule that contains electrons. It is crucially important in governing molecular reactivity and properties.

When a molecule acts as a Lewis base (an electron pair donor) in bond formation, the electrons are supplied from the molecule's HOMO.

Readiness to donate electrons is reflected in the energy of the HOMO. Molecules with high HOMOs are more able to donate their electrons and are hence relatively reactive compared to molecules with low-lying HOMOs. Thus descriptor HOMO should measure the nucleophilicity of a molecule.

Lowest unoccupied molecular orbital energy (LUMO)

It is the lowest energy level in the molecule that contains no electrons. When a molecule acts as a Lewis acid (an electron pair acceptor) in bond formation, incoming electron pairs are received in its LUMO. Molecules with low-lying LUMOs are more able to accept electrons than those with high-energy LUMOs. LUMO measures electrophilicity of a molecule.

Superdelocalizability (Sr)
An index of reactivity in aromatic hydrocarbons (AH), proposed by Fukui.

Sr ej cjr m

= superdelocalizability at position r = bonding energy coefficient (eigen value) in jth MO = molecular orbital coefficient at position r in jth MO = index of the HOMO

Index of HOMO (m)

Based on the idea that

early interaction of the MOs of 2 reactants may be regarded as a mutual perturbation,
overlap as so that the relative energies of the 2 orbitals change together and maintain a similar degree of the reactants approach one another.
Energy & Perturbation

Considering the interaction of the MOs of the separated reactants,

Get the additional assumptions that

this is a prediction of the height of the transition state barrier at position r, and

the greatest interaction will occur at the site of largest orbital density, that is, largest c2.

Concept of delocalizability - ej
For low-lying levels(LUMO), ej - bonding energy value is large and +ve

Interpret this as, the electrons are tightly held

Not very delocalizable
For upper occupied states (especially HOMO),ej is much smaller Electrons in the higher-energy orbitals are less tightly bound Relatively delocalizable

-ve Energy value is small

+ve Energy value is large

Therefore the upper energy levels will dominate the Superdelocalizability term. Summing Sr for all atomic positions of a molecule gives an idea of electrophilicity, which may be used to predict relative reactivity in a series of molecules.

4. Fragment constants descriptors

These are constants that relate the effect of substituents on a "reaction center" from one type of process to another.
X O M P X = electron donating or withdrawing groups nitration X

Basic idea: Similar changes in structure are likely to produce

similar changes in reactivity, ionization, or binding.
There are different constants corresponding to different effects.

These are typically used to parameterize the Hammett (or Hammett-like) equation for some series of analogs.

Kx is the rate constant of the derivative

(fit to the set of analogs being studied) the rate of different reactions depends on the electron release or withdrawal of the substituents

Kh is the rate constant for the parent

x refers

to the electronic effect of the substituents relative to hydrogen (ionization constants)

Sm, Sp Electronic effect Sigma meta and Sigma para, respectively. +ve values correspond to electron withdrawal ve values to electron release Sigma is generally not appropriate for ortho substituents because of steric interaction with the reaction center. F, R
X O M P X = electron donating or withdrawing groups

When the substituent is conjugated with the reaction center producing through-resonance effects, Decompose of sigma para (Sp) constant into an inductive (polar) part (F) and a resonance part (R)

pi Hydrophobic character. piX = logPX logPH LogP = The partition co-oefficient in Octanol/water medium

HA
Hydrogen bond acceptor.

HB Hydrogen bond donor.

MR Molar refractivity n MW d refractive index molecular weight, and density

The molecular refractivity index of a substituent is a combined measure of its size and polarizability.

Sterimol-L
Steric length parameter, measured along the substitution point bond axis.

Sterimol-B1 through B4 Steric distances perpendicular to the bond axis. These define a bounding-box for the substituent and are numbered in ascending size order.

Sterimol-B5
The overall maximum steric distance perpendicular to the bond axis.

5. Thermodynamic descriptors
The following lists of thermodynamic descriptors are available: AlogP Fh2o Foct Hf MolRef Log of the partition coefficient Desolvation free energy for water Desolvation Free Energy for Octanol Heat of formation Molar refractivity

AlogP and Molar Refractivity (MolRef)

These can be used to relate chemical structure to observed chemical behavior.

LogP -hydrophobic character of the molecule.

The molecular refractivity of a substituent is a combined measure of its size and polarizability. The descriptor ALogP and molar refractivity are calculated using the loaded values in the data file (which are having different classes according to the nature of the atoms).

In this atom-based approach, each atom of the molecule is assigned to a particular class, with additive contributions to the total value of logP and molar refractivity.

Desolvation free energy for water (Fh2o) and octanol (Foct)

Foct and Fh2o are physiochemical properties associated with a molecule. Proven useful as molecular descriptors in SAR. All computations are based on connectivity of the atoms. Computations are not conformationally dependent. Foct is the 1-octanol desolvation free energy FH2O is the aqueous desolvation free energy Derived from a hydration shell model, where Fh2O and Foct are in kcal/mol

The values for some functional groups and as well as atoms in a specific environment are:

GROUP
1.CH3 (Methyl-ali) 2.O (Hydroxyl-ali) 3.CH2 (Methylene-ali) 4.CH (Methine-ali) 5.C (t-butyl-ali) 6.N (Nitro) 7.C= (Vinyl) 8.F (ali-single) 9.Cl (ali-single)

FH2O FOCT
0.800 -5.820 0.200 -0.240 -0.720 11.910 -0.330 0.800 -0.940 -0.160 -3.790 -0.520 -0.560 -0.920 11.840 -0.970 1.430 -1.020

Program calculates FH2O and FOct for each molecule Search the molecule for recognizable substituent groups and their bonding patterns Summing the substituent constants contributions for each group that is present in the molecule

Heat of formation (Hf)

An enthalpy gained in forming a molecule from its constituent atoms. It is a measure of the relative thermal stability of a molecule. This descriptor is calculated using the MNDO (Modified Neglect of Diatomic Overlap).
The most rigorous quantum-chemical technique available. It has a wide range of applicability in conformational analysis, intermolecular modeling, and chemical reaction modeling.

Atoms treated by MNDO: H, B, C, N, O, F, Al, Si, P, S and Cl