CADD
Pharmacophore Modeling
in Drug Design
Presented by – Joshi Aishwarya Rajendra
1st year, M. Pharmacy
Roll no. - 04
Subject - CADD ( MPC 203T )
Dept. – Pharmaceutical Chemistry
Guidance by – Manoj G. Damale
Institute – Srinath College Of Pharmacy, Chh.
Sambhaji Nagar.
Content
1. Pharmacophore
2. Advantages
3. Historical Perspectives
4. Pharmacophore Model Development
5. Steps in Pharmacophore Development
6. Identification of Pharmacophore Using Software
7. 2 D pharmacophore
8. 3 D pharmacophore
9. Ligand based pharmacophore mapping
10. Structure based pharmacophore mapping
11. Process of pharmacophore mapping
12. Pharmacophore modelling steps
13. Pharmacophore based screening
14. Structure based virtual Screening
15.
Pharmacophore
What is
Pharmacophore?
A pharmacophore is the minimum set of structural and chemical
features in a molecule that are essential to ensure its interaction with a
specific biological target and produce a desired biological response.
These features can include:
1. Hydrogen bond donor (HBD) – e.g., –NH₂, –OH groups.
2. Hydrogen bond acceptor (HBA) – e.g., C=O, N atoms.
3. Aromatic rings – involved in π–π stacking or hydrophobic
interactions.
4. Hydrophobic groups – e.g., –CH₃, aromatic rings.
5. Positively/negatively charged groups – ionic interactions.
Example: In β-adrenergic blockers, the hydroxyl group (HBD),
amine group (positively charged), and aromatic ring are critical
pharmacophoric elements.
Advantages of Pharmacophore
1.Identifies essential features
2. Guides new drug design
3. Supports virtual screening
4. Explains Structure–Activity Relationship (SAR)
5. Flexibility in drug discovery
6. Discovery of novel scaffolds
7. Integration with computational tools
8. Reduces experimental workload
Historical Perspectives
Paul Ehrlich (1909): Proposed the concept of a “magic bullet” – a chemical entity
that selectively targets pathogens without harming the host. This idea laid the
foundation for pharmacophore theory.
1930s–1960s: Scientists started correlating chemical structures with biological
activity → Structure–Activity Relationship (SAR) was developed.
1970s: Term “pharmacophore” was formally introduced, emphasizing the 3D
arrangement of features.
Modern era (1990s onwards):
Advanced X-ray crystallography & NMR revealed protein 3D structures.
Computational tools now allow precise pharmacophore modeling and virtual
screening of large chemical libraries.
Pharmacophore model development
The purpose of developing a pharmacophore model is to:
1. Identify the key molecular features responsible for
activity.
2. Understand how these features are arranged in 3D space.
3. Use the model to design or search for new drug
candidates.
Steps in Pharmacophore Development
Step 1: Identify common Step 2: Generate Step 3: Define 3D
binding features conformations relationships
Collect a set of active Molecules are flexible; they Measure distances, angles, and
compounds (with known can adopt many 3D orientations between
activity). shapes.Use pharmacophore features.
Compare their structures to find computational tools to Example: A hydrogen bond
common chemical groups generate all possible donor may need to be 5 Å
responsible for binding. conformations.Each away from an aromatic ring
Example: All COX-2 inhibitors conformation is analyzed for activity. This 3D
have an aromatic ring and to see if it can fit into the arrangement forms the
sulfonamide group. binding site. pharmacophore
hypothesis.
Identification of Pharmacophore Using
Software
Pharmacophore Mapping Software:
Used to create pharmacophore models from active compounds.
Examples: Discovery Studio (HypoGen), LigandScout, Phase
(Schrödinger), MOE, Catalyst.
Conformation Search Software: Used to generate all possible 3D
conformations of molecules.
Examples: OMEGA, Cerius², Catalyst.
Similarity-Based Methods
1. Based on the principle: “similar structure → similar activity.”
2. If a molecule looks like a known drug, it might act in the same way.
3. 2D similarity: compares flat structures (fingerprints, chemical features).
4. 3D similarity: overlays molecules in 3D to compare shape and features.
Example: If ibuprofen is active, similar compounds might also be anti-
inflammatory.
2 D Pharmacophore
1. Flat (2D) diagram of a molecule’s key
features.
2. Shows: hydrogen bond donors, acceptors,
hydrophobic groups, etc.
3. Helps identify essential groups for
protein/receptor binding.
4. Useful for designing new molecules with
better activity.
Antispasmodic Drug
(xanthone derivatives)
3 D Pharmacophore
1. 3D arrangement of important features in space.
2. Shows donors, acceptors, hydrophobic regions, aromatic rings.
3. Considers actual shape of ligand and protein.
4. More accurate than 2D; predicts binding & selectivity better.
5. Used in virtual screening, drug discovery, lead optimization.
6. Built using computational tools (e.g., molecular docking).
(a)The generated hypothetical 3D-
pharmacophore geometry with four
features; two HBA (red) and one
hydrophobic (yellow).
(b) Mapping of the co-crystallized
ligand on the generated pharmacophore
(Fit value = 36.08).
(c) The calculated distances between
the different features.
3D Pharmacophore Image
Difference between 2D & 3D Pharmacophore
2D Pharmacophore 3D Pharmacophore
● Spatial, 3-dimensional
● Flat, 2-dimensional ● Shows both features and their
● Shows functional groups only spatial arrangement
● Less accurate ● More accurate & realistic
● Quick understanding of key groups ● Better prediction of binding &
● Ignores 3D shape of molecule activity
● Requires structural data & more
computation
Ligand-based Pharmacophore Mapping
Used when protein structure is unknown.
Compares multiple active ligands to find common features.
Types:
1. Shared feature pharmacophore
2. QSAR-based pharmacophore
Software: LigandScout, Discovery Studio Catalyst, MOE.
Structure-based Pharmacophore Modelling
1. Used when protein 3D structure is known.
2. Identifies complementary features of protein active site.
Types:
1. Macromolecule–ligand complex-based
2. Macromolecule-based (protein only)
Software: e-Pharmacophore, Discovery Studio Catalyst.
Process of Pharmacophore Mapping
1. Data Collection – Gather ligands known to bind the target.
2. Alignment – Arrange ligands to highlight common features.
3. Feature Identification – Identify important groups (hydrogen bond
donors/acceptors, hydrophobic regions, aromatic rings, etc.).
4. Pharmacophore Generation – Create a model showing the 3D
arrangement of these features.
5. Validation and Optimization – Test the model against experimental
data and refine it for accuracy.
6. Virtual Screening – Use the model to search chemical databases for
new potential drug candidates.
7. Lead Optimization – Modify selected compounds to improve
binding strength and selectivity.
Process of pharmacophore modelling
1. Feature Selection – Choose the essential features responsible for
activity.
2. Feature Geometry – Define the relative positions and distances
between these features.
3. Model Generation – Build the 3D pharmacophore model.
4. Validation – Test with active and inactive compounds to ensure
reliability.
5. Virtual Screening – Screen large compound libraries to find new
drug candidates.
Pharmacophore-Based Screening
Instead of comparing whole molecules, only the pharmacophore
features are used.
Steps:1. Build pharmacophore model.
2. Screen compound libraries to find molecules that fit.
3. Rank hits by “fit score.”
4. Select top hits for experimental testing.
Advantage: Can find completely new scaffolds that still fit the
same pharmacophore.
3D Pharmacophore-
based virtual
screening workflow
What is Virtual Mapping?
Virtual Screening: Computer-based selection of compounds from
databases by comparing them to a pharmacophore or protein binding
site.
Virtual Mapping: Overlaying molecules on a pharmacophore model to
see if they fit.
Example: COX-2 inhibitor pharmacophore used to screen chemical
libraries → millions of compounds tested virtually, top hits tested in
labs → discovery of new anti-inflammatory drugs.
Reference
1. Patrick, G. L. An Introduction to Medicinal Chemistry; 3 rd ed.; Oxford
University Press: Oxford, 2005; pp 340–345.
2. Wikipedia contributors. Pharmacophore. Available online:
https://en.wikipedia.org/wiki/Pharmacophore (accessed Aug 17, 2025).
3. AuthorStream Guest. Pharmacophore Mapping. Available online:
http://m.authorstream.com/presentation/aSGuest126841-1335009-pharmac
ophore-mapping/
(accessed Aug 17, 2025).
Thank You !!
