3D QSAR Introduction to 3D QSAR 3D QSAR Approaches 1. Stereochemistry and drug action 2. Active site interaction 3. Comparative molecular field analysis comfa comsia Counter Map Analysis Importance Contour plots of the CoMFA

1. 3D QSAR
Presented by
Swapnil G. Ugle
M. Pharm. 1st Year
Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur.

2. Contents:
• Introduction to 3D QSAR
• 3D QSAR Approaches
1. Stereochemistry and drug action
2. Active site interaction
3. Comparative molecular field analysis
• Counter Map Analysis
• Importance

3. Introduction of 3D QSAR
• QSAR deal with interactions of molecules in 3D shape.
• CoMFA (Comparative Molecular Field Analysis) & CoMSIA
(Comparative Molecular Similarity Index Analysis) are the
two methodolgies adopted.
• Molecules are described by the values of molecular fields
(properties) calculated at points in a 3D grid.

4. • Drug- Receptor interactions usually don't involve
covalent bonds.
• Usually only the steric and electrostatic forces defines
molecular properties.
• Lipophilic/hydrophilic parameters are not considered.
• 3D QSAR – Partial Least Square Analysis (PLS).
• 2D QSAR – Least Square Reggration.
• A common pharmacophore is required for all the
selected sets of compounds under the study.

5. • Physical properties are measured for the molecule as a
whole.
• Properties are calculated using computer software.
• Properties are known as 'Fields’.
Steric field - Size and shape of the molecule.
Electrostatic field - Eelectron rich/poor regions.
• Hydrophobic properties are relatively unimportant.
Pharmacophore

6. • A probe atom is placed at each grid point.
• Probe atom = A proton or sp³ hybridised carbocation.

7. Advantages
• No reliance on experimental values.
• Can be applied to molecules with unusual substituents.
• Predictive capability.
• Not restricted to molecules of the same structural class.

8. 3D-QSAR Approaches
1.STEREOCHEMISTRY
2.ACTIVE SITE INTERACTION
3.COMPARITIVE MOLECULAR FIELD ANALYSIS (CoMFA)

9. STEREOCHEMISTRY AND DRUG ACTION
• Stereochemistry of drugs plays an important role for the biological
activity.
• According to Ariens and Lehman, chirality has an important
influence on biological activity.
• This situation is even worse in diastereomeric mixtures because the
relative amounts of the different racemate in the mixture vary
largely.

10. ACTIVE SITE INTERACTION:
• Depends on the pharmacophore and active site properties.
• 3D-QSAR can determine the tentative interactions.
• Pharmacophore pattern searching, receptor mapping at the
different positions of the ligand, form the ligand with
restricted internal rotations (rigid analogues)etc.
• Example- n-propane for aliphatic amino acids, acetamide for
amide side chains, methanol for serine, toluene for aromatic
amino acids etc.

11. COMPARATIVE MOLECULAR FIELD ANALYSIS
• CoMFA is the 3D-QSAR approaches that furnish information
about the drug-receptor interactions.
• It is developed by Deack Crammer in 1988.
• It involves placing of molecules in a grid and to correlate field
properties of the molecules with biological activities.
• CoMFA is an alignment dependent, descriptor-based method, all
aligned ligands are placed in their computed values which serve
as descriptors for model development.
• These descriptor values are then correlated with biological
responses employing Partial Least Squares Analysis(PLS).
• The PLS results indicates favorable and unfavorable
electrostatic and steric potential and also correlate it with
biological responses.

12. Counter Map Analysis
• CoMFA - Comparative Molecular Field Analysis
• The results of CoMFA gieves counter plots showing the
regions in space where specific molecular properties
increases or decreases.
• The counter are colored in green and yellow for positive and
negative steric effects respectively while blue and red for
positive and negative electrostatic effects respectively.
• Positive steric counter define the region where substituent
size is proportional to biological activity and negative steric
countoer highlights the area where substituents decreases
the potency.

13. Contour plots of the CoMFA steric fields (left) and
electrostatic fields (right)
Blue – Positive electrostatic effect
Red – Negative electrostatic effect
Green - Steric effect

14. IMPORTANCE
• It is used in Computational drug designing.
• One of most significant and widely used method is using
software computed descriptor in QSAR technique.
• It can predict energy related properties such as electronic,
spectroscopic properties for molecule.
• It is used for prediction of molecular weight, counts of atom,
bonds and rings, connectivity of molecule.
• Used in structural analysis

15. References:
• B. J. Jaidhn , P. Srinivasa Rao, Allam Apparo. Energy Minimization &
Conformation Analysis of Molecule using Conjugate Gradient Method
IJRET. 2014; 2: 124
• Thomas J. Perun, C.L. Propst. Computer Aided Drug Design method &
Application. Marcel Dekker , Inc., New York: 1983; 70-72.
• Foye’s Principles of MEDICINAL CHEMISTRY. Wolters Kluwer (India)
Pvt. Ltd., New Delhi. 2008; 06; 167

16. Thank you ...