Steps in QSAR Model Generation:

1. Preparation of input data (structures, known biological activities)

2. 3D Geometry optimization (conformation generation, alignment)
3. Calculation of descriptors
4. Statistical Analysis (Feature selection, regression)
5. QSAR model building
6. Interpretation, validation and prediction Structure optimization
1.100,000 atoms: Molecular mechanics Use of empirically derived potential function
2.1000 atoms: Semi-empirical quantum mechanics Use of approximate Schrodinger equation
3.100 atoms:Ab initio quantum mechanics Solve exact Schrodinger equation Descriptor
Calculation and Statistic Software for QSAR:
1. ADAPT
2. TSAR
3. SciQSAR
4. Cerius2
Statistical Packages
1. SAS
2. SPSS
3. Minitab
4. STATISTICA
5. SYSTAT
6. StatView
7.WinNN (Neural Networks)
Conformational Search:
1. Grid Search
2. Random Search
3. Boltzman Search
4. Systematic Search
Alignment of Molecules
1. RMS atoms alignment - pairwise model alignment based on superimposition
2. Moments alignment using electrostatic moments or principle moments of inertia
3. Field alignment maximizing the overlaps between steric and electrostatic felds
calculated using probe potential
Selection of Descriptors
1.QSAR model should be reduced to a set of descriptors which is as information
rich but as small as possible
2.Rule of thumb: 5-6 structural points should fall per structural descriptors
3. Objective selection
a. Correlations
b. Pairwise selections
c. Identical tests
d.Vector space descriptor analysis
4. Subjective selection
a.Descriptor selection considering biological activity
b.Genetic algorithm based feature selection
Statistics in QSAR
1.Multiple linear regression:

Least square error minimization

N, ANOVA, R, F test, p value

Examine multi-collinearity: tolerance=1-R2, VIF=1/(1-R2)

Yields linear models with coefcients that can be interpreted for relative
importance
2.Step-wise multiple linear regression

Forward, backward, stepwise
3. Principle components regression analysis
4. Partial least square analysis
5. Artifcial Neural Network method
6. Genetic function approximation
7. Principle component analysis
8. Factor analysis
9. Discriminant analysis
10. Cluster analysis