3D QSAR

COMFA
 COMFA
• Comparative Molecular Field Analysis
“ Drug receptor interactions are non covalent
Changes in steric or electrostatic fields correlates with
the changes in biological activity”
 COMFA - steps
• 1. Defining steric and electrostatic fields
• 2. Correlating with biological activity
1. Defining steric and electrostatic fields

• 3D model generation for molecule

• Define active conformation from the stable
conformations
• Energy minimization
• identify a 3D Pharmacophore
1. Defining steric and electrostatic fields
Pharmacophore refers to a set of features that is
common to a series of active molecules
Typical pharmacophoric features are
(a) Hydrogen bond donors and acceptors
 (b) Positively and negatively charged groups
 (c) Hydrophobic groups
A 3D-pharmacophore specifies the special
relationship between the group in terms
distances, angles and planes
 1. Defining steric and electrostatic fields

4 .2 – 7 .3 Å

.. N

4 .9 – 7 .3 Å

[C,N]

• Antihistaminic 3D pharmacophore features: two aromatic rings and a tertiary

nitrogen
1. Defining steric and electrostatic fields

• Placing the pharmacophore in grid

1. Defining steric and electrostatic fields

• Measuring steric and electrostatic fields

• Placing a probe
– carbon (sp3) steric interactions
– pos. charged carbon electrostatic interact.
– hydrogen/oxygen H-bond interactions
• Calculate steric and electrostatic interaction
between probe and
1. Defining steric and electrostatic fields
Table 1: Representation of data structure in CoMFA analysis
Compd Steric field Electrostatic field Activity
S1 S2 S3----SN E1 E2 E3---- EN
1      
2
3.
n
 2. Correlating biological activity
• Caluculated steric and electrostatic interaction
at each grid point- variables
• Large number of variables
• Not possible to use MLRA(as in traditional
QSAR)
• PLS
Table 1: Representation of data structure in CoMFA analysis
Compd Steric field Electrostatic field Activity
S1 S2 S3----SN E1 E2 E3---- EN
1      
2
3.
n

Activity = a1S1 + a2S2 + -- aNSN + b1E1 + b2E2 + ---bNEN

+ constant
SN and EN refers to steric and electrostatic fields,
respectively, N stands for the number of grid points
The above relationship is obtained using partial least
square method
• PLS
– Formula(relationship)
– Cross validation
– New formula(improved)
– Cross validated correlation coefficient r2
– Should be greater than 0.8
Stereoview of CoMFA contour: (a) Steric fields, with green
indicating favorable contribution, and with yellow indicating
detrimental effects; (b) Electrostatic fields, with blue indicating +ve
fields (unfavorable) and with red indicating –ve fields (favorable).