The document discusses conformational analysis and its applications. It begins with an introduction to conformational analysis, how conformations are different spatial arrangements of atoms in a molecule. It then discusses conformational sampling and optimization methods. Next, it covers similarity measures and cluster analysis used to analyze conformational ensembles. An example of conformational analysis of an anti-inflammatory drug is provided. The document concludes with applications of conformational analysis in areas like protein structure determination, drug design, and QSAR modeling.

1. Presented by
Nilesh More (MC-2019-14)
Department of Medicinal Chemistry
NIPER HYDERABAD

2. FLOW OF PRESENTATION
INTRODUCTION CONFORMATION
ALANALYSIS
ALIGNMENTS IN
3D-QSAR
APPLICATIONS
CONCLUSION

3.  INTRODUCTION
 The most important concerns in medicinal chemistry and pharmaceutical research are structure
elucidation, conformational analysis, physicochemical characterization and biological activity
determination.
 Conformational search methods find applications in the design of targeted chemical hosts and drug
discovery
 Conformations are different 3D spatial arrangements of the atoms in a molecule are interconvertible by
free rotation of single bonds
 The major objective of conformational analysis is to gain insight on conformational characteristic of
flexible biomolecules and drugs but to also identify the relation between the role of conformational
flexibility and their activity.
 The significance of conformational analysis not just extends to computational docking and screening but
also for lead optimization
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4.  Conformational Analysis
 DHR barton is considered the most important contributor to
modern conformational analysis.
 In 1950, he showed how various substituents at the equatorial
and axial positions affect the rate of reactivity of substituted
cyclohexanes.
 Identification of all possible minimum- energy structures
(conformations) of a molecule is the goal of conformational
analysis
 Conformational analysis is a difficult problem because even
simple molecules may have a large number of conformational
isomers
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5.  Conformational Sampling
 Conformation sampling is a procedure used to create
a collection of molecular conformations that will
later be analyzed.
 As the size of the molecule increases, the number of
locally stable conformations increases
 The basic criterion is that the resulting
conformational sample ‘‘ensemble’’ will be
representative of the system as a whole
Methods
Systematic Search method
Random Searches
Neural Networks
Molecular dynamics
Model Building Approaches
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6.  Conformational Optimization
 The various sampling procedures result in a number of
transient conformations
 During energy minimization of these structures is to
bring these conformations to the minima before analysis
is performed
 Stimulated annealing is used in optimization problems
where minimization of objective function can be carried
out
 It is designed for finding the samples low energy
conformations more sharply
 It is derived by analogy with the process of
crystallization
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7.  Conformational Analysis
 Collection that was sampled and optimized is
essential so as to ascertain the conformational
properties of the molecule
 This helps to underline the properties and
exemplify features of overall flexibility and
common inclination in the conformation set
 Alternatively, it may be used to identify a smaller
subset of characteristic low energy conformations
 This helps in future drug development programs
Conformational
Analysis:
Similarity Measures Cluster Analysis
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8. A. Similarity Measures
 Essential for quantitative comparison of one structure with
another and it must be defined before the analysis
 Structural similarity is calculated by a root-mean-square
distance (RMSD) between two conformations.
 In cartesian coordinates the rms distance dij between
conformation i and conformation j of a given molecule is
defined as the minimum of the functional
 Where, N is the number of atoms in the summation, k is an
index over these atoms, rk
(i) , rk
(ij) are the cartesian
coordinates of atom k in conformations i and j
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9. B. Cluster Analysis
 A regular investigative technique used to group conformations
 Structural similarity are highlighted and are defined by the distance
measure being used within a conformational sample
 The initial conformation selected is generally of low energy and all
conformations that are contained a given cutoff distance from this
structure are grouped together to form first cluster
 The ungrouped conformations are selected and second cluster is
formed
 Procedure is repeated until all conformations are assigned into
clusters
 Lowest energy confirmation is picked from cluster and then used as
basis for generating pharmacological hypothesis for drug
development
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10.  Conformational analysis of the anti-inflammatory Agent amfenac
 Molecular models of the minimum-energy
conformations of amfenac, as derived from the
conformational analysis
 A-D show the rotation of the benzoyl group
 E-H show the rotation of the acetic acid chain
 The most likely bioactive conformation (E) was
selected as structurally similar to the arachidonic acid
in its active form
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11.  ALIGNMENT OF MOLECULE IN 3D-QSAR
 Alignment is a crucial component in 3D QSAR
studies
 Two independent molecular alignment procedures
were used in the present study
I. Rigid-body fit
II. Receptor-based
 The analyses are highly dependent on the quality of
the alignments
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12. • The lowest energy conformer
was used as the template structure
for the molecular alignment
• lowest energy conformations
were superimposed on the
template molecule using an
atom/centroid root mean square
(RMS) fitting procedure
• The alignment and maximal
common substructure used for
superposition are illustrated in
Figure .
Rigid-body fit.
Figure: Three-dimensional data set alignment of Discodermolide
 Anticancer Activity of a Series of β-Tubulin Ligands
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13.  Class of IKK-2 Inhibitors
 A. Pharmacophore-based molecular alignment by using
GALAHAD
 Coloured spheres represent different pharmacophore feathers
i. Cyan for hydrophobic centre
ii. Green for hydrogen-bond donor
iii. Magenta for hydrogen bond acceptor
 B. The molecular alignment by using classical common
structure method
 C. The binding pocket of IKK-2 homology model with
compound which adhere to the pharmacophore features
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Used in the refinement of x-ray and NMR data to determine the three
dimensional structures of large biological molecules such as protein,
automated docking of substrates to proteins and thus in protein
engineering
Receptor modeling, particularly regarding the binding of small ligand
molecules to sites of proteins or macromolecules
Design and analysis of compound library generation of quantitative
structure–activity relationships (QSAR) models
01
02
03
 APPLICATIONS

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 CONCLUSION
Different combinations of these methods can also be used in combination to
perform complete conformational analysis of any molecule
With enormous generation of data and increased synthesis and isolation
of new compounds, conformational analysis is an essential part so that
systemic interpretation and representation of data is made possible

16.  REFERENCES
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Research. 2013 Jan 1;4(1):34.
Ruiz J, Lopez M, Mila J, Lozoya E, Lozano JJ, Pouplana R. QSAR and conformational analysis of the
antiinflammatory agent amfenac and analogues. Journal of computer-aided molecular design. 1993 Apr;7(2):183-
98.
Zhang X, Mao J, Li W, Koike K, Wang J. Improved 3D-QSAR prediction by multiple-conformational alignment:
A case study on PTP1B inhibitors. Computational biology and chemistry. 2019 Dec 1;83:107134.
Salum LB, Dias LC, Andricopulo AD. Structural and chemical basis for anticancer activity of a series of²-tubulin
ligands: molecular modeling and 3D QSAR studies. Journal of the Brazilian Chemical Society. 2009;20(4):693-
703.
Long W, Liu P, Li Q, Xu Y, Gao J. 3D‐QSAR Studies on a Class of IKK‐2 Inhibitors with GALAHAD Used to
Develop Molecular Alignment Models. QSAR & Combinatorial Science. 2008 Sep;27(9):1113-9.
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