The document discusses the superimposition method in drug design, which aligns the 3D structures of molecules to identify similarities crucial for understanding biological activity. It outlines three alignment methods: rigid, semi-flexible, and flexible, each with its specifics on how to handle conformations. The use of the method in 3D QSAR studies is emphasized, highlighting its role in developing pharmacophore hypotheses and validating models.

1. SUPERIMPOSITION
METHOD
Presented by:-
Ishpreet Singh
M.S.(PHARM.)
16PIM2463
DEPARTMENT OF
PHARMACOINFORMATICS
NIPER MOHALI

2. DEFINITION:-
Superimposition is a method used
in drug designing to establish a
common alignment of 3D
structures of investigated
molecules.

3. REQUIREMENT FOR SUPERIMPOSITION
 It is an important task in drug design to identify similarities of 3D
structures of compounds that share similar biological activities,
especially when the 3D structure of the macromolecular target
molecule is not known.
 Ideally, the ligands should bind to the same biological target within the
same cavity of the molecule. Otherwise the deduced model will be
misleading.
 In order to reach this the 3D structures of the small ligand molecules
are aligned to identify geometrical similarities and related spatial
arrangements of chemical features.

4. Contd..
 If this results in a plausible overlay it can be used
for 3D-QSAR analyses to correlate the obtained
conformations with the biological activity.
 superimposition step is a crucial step for
following analyses comprising e.g.
i) pharmacophore evaluation
ii) receptor modeling
iii) ligand-based virtual screening
iv) 3D-QSAR examination

5. Classification of superimposition or alignment
method
 Rigid alignment method
 Semi-flexible alignment method
 Flexible alignment method

6. Rigid alignment method
 The approach for rigid-body alignment tries to
maximize similarity of surface descriptors,
generally given through Gaussian functions,
approximating different properties, such as van
der Waals overlap, electron density overlap. In
this technique , we directly try to overlap one
molecule over the other without any
conformational or substituent change.

7. Semi-flexible alignment method
 To allow the screening of different conformations
for one molecule some approaches apply
conformation generation methods.
 In this method, they compare sets of
precomputed conformations for one molecule in
advance and afterwards perform a rigid body
alignment of the generated conformations. Hence
the name semi-flexible analysis.

8. Flexible alignment method
 A method is presented for flexibly aligning small
molecules. The method accepts a collection of small
molecules with 3D coordinates as input and computes a
collection of alignments. Each alignment is given a score,
which quantifies the quality of the alignment both in
terms of internal strain and overlap of molecular features.
 RMSD(Root Mean Square Deviation) of atomic positions is
the measure of the average distance between the atoms
of superimposed molecules.
 RMSD is used for estimation of divergence of the two
aligned molecules.

9. Application of superimposition method
 Superimposition method is employed in 3D QSAR studies in which
CoMFA (comparative molecular field analysis ) describing 3D structure
activity relationships in a quantitative manner is used.
 In this method, set of molecules is first selected which will be
included in the analysis. A certain subgroup of molecules is selected
which constitutes a training set to derive the CoMFA model. The
residual molecules are considered to be a test set which
independently proves the validity of the derived models .
 A pharmacophore hypothesis is derived to orient the superposition of
all individual molecules and to afford a rational and consistent
alignment.
 Estimation of the energy values which the probe would experience in
the corresponding position of the regular 3D lattice .

10. References
 Sen, Sandip, N. A. Farooqui, T. S. Easwari, and Bishwabara Roy.
"CoMFA-3D QSAR approach in drug design." (2012).32-36
 R. D. Cramer III, D. E. Patterson, and J. D. Bunce, "Comparative
molecular field analysis (CoMFA). 1. Effect of shape on binding of
steroids to carrier proteins", J. Am.Chem. Soc.1988, 110, 5959-5967.
 C. Lemmen and T. Lengauer, "Computational methods for the
structural alignment of molecules", J. Comput. Aided Mol. Des. 2000,
14, 215-232

11. Thankyou…