3D QSAR Methods

Steps for Drug Designing

• ISIS Draw 2.3
• ChemSketch 8.0. LIGAND PREPARATION
• LigPrep (Schrodinger, 2007)
• Tatutomers, steric isomers and geometry
minimization
• PROTEIN PREPARATION
Minimization by MMFF with default setting
• Target protein
• Chains extraction.
• Hydrogens were added via the Maestro interface DOCKING
(Schrodinger, 2007)
• Removed water molecules
• Final preparation was using PPrep (Schrodinger GLIDE SP
2007)
• Minimization by OPLS-2005 force field (Polak et al.,
1969) was stopped either after 5000 steps or after
the energy gradient converged below 0.05 kcal/mol. GLIDE XP
• Docking by Glide 4.0 (Halgren, 2004).
• Glide SP (single precision mode).
• Glide XP (extra precision mode). LSBD
 Ligand & Structure Based Descriptor (LSBD)
(Schrodinger, 2008)

• The Ligand & Structure-Based Descriptors panel provides a convenient

interface to several Schrödinger programs, which are used to generate
descriptors for a QSAR model.

• The focus is on generating descriptors for a set of ligands that are docked to
a receptor. Three of the programs, Liaison, Prime MM-GBSA, and the
eMBrAcE module of MacroModel, operate on the ligand and the receptor.
The other two, QikProp and Ligparse, operate on the ligand only.
•
• The descriptors extracted from Liaison, Prime MM-GBSA, and eMBrAcE are
energetic properties related to ligand binding. QikProp generates ADME
properties, and Ligparse generates structure based properties such as
functional group counts. These descriptors can be used as input to the
model-generation facility in Strike.
3D QSAR Methods (Phase, version 2.0.212; Schrodinger, LLC: New York, 2005)
 3D QSAR
• CoMFA and CoMSIA (Comparative Molecular Field Analysis and
Comparative Molecular Similarity Indices Analysis)

– Molecules are described by the values of molecular fields

calculated at points in a 3D grid
– The molecular fields are usually steric and electrostatic
– Partial least squares (PLS) analysis used to correlate the field
values with biological activity
– A common pharmacophore is required.
 PLS (Partial least Square)
Partial least squares regression (PLS regression) is
a statistical method that bears some relation to
principal components regression; instead of finding
hyper planes of minimum variance between the
response and independent variables, it finds a linear
regression model by projecting the predicted variables
and the observable variables to a new space.

Because both the X and Y data are projected to new

spaces, the PLS family of methods are known as
bilinear factor models.
 Using the Model

• The PLS results are presented as

contour plots
• Steric Bulk:
– Green = Steric Favourable
– Yellow = Steric Unfavourable
• Electrostatics:
– Red = Electronegative
Favourable
– Blue = Electronegative
Unfavourable
 3D-QSAR CoMFA Study on Aminothiazole Derivatives as Cyclin
Dependent Kinase 2 Inhibitors

• In this work we performed CoMFA study carried out on 47

aminothiazole derivatives as inhibitors of this protein kinase.
• The models could be usefully employed to design selective CDK2
inhibitors and to find novel scaffolds through screening of chemical
databases.

Allignment
 CoMFA Steric Contours CoMFA Electrostatic Contours

• Green contours stand for points where sterically bulkier groups are anticipated
to increase the biological activity.
• The yellow contours are used to underscore the points where bulkier groups
could lower the biological property.
• The electrostatic red plots show where the presence of a negative charge is
expected to enhance the activity.
• The blue contours indicate where introducing or keeping positive charges are
expected to better the observed activity.

• 3D-QSAR CoMFA Study on Aminothiazole Derivatives as Cyclin Dependent Kinase 2

Inhibitors. Nigus Dessalew, Sanjeev Kumar Singh* and P.V. Bharatam QSAR Comb. Sci.,
26(1), 2007, 85-91.