Introduction
This post is Part 2 of Unit I – Basic Considerations of Drug Activity from the Introduction to Medicinal Chemistry paper of MSc Chemistry 4th Semester (BAMU University syllabus).
In Part 1, we studied basic terms like drug, prodrug, agonist, antagonist, potency, efficacy, pharmacophore, and LD₅₀–ED₅₀, which form the foundation of medicinal chemistry.
In this Part 2, we move one step deeper and understand how drugs actually show activity in the body.
This post explains:
Factors affecting bioactivity
Theories of drug activity
Structure–Activity Relationship (SAR)
QSAR (2D & 3D)
Drug–receptor mechanism and Hantzsch equation
All concepts are explained in very simple language with exam-oriented points, making it easy for BAMU students and MSc Chemistry students of other universities to understand and revise.
Factors Affecting Bioactivity
Bioactivity refers to how a drug or chemical affects living organisms. Several factors influence bioactivity, including chemical structure, interaction with biological targets, and how the body processes the drug.
1. Chemical Properties
• Lipophilicity (Fat Solubility): Drugs that dissolve in fat easily cross cell membranes, but too much
lipophilicity can cause toxicity.
• Solubility: Drugs must be water-soluble for good absorption in the body.
• Molecular Size and Shape: Small molecules enter cells easily, while large ones need transport
systems.
• Ionization and pKa: Affects drug absorption in different body parts (stomach vs. intestines).
2. Structural Features
• Functional Groups: Parts of the molecule (like -OH or -NH₂) affect drug action.
• Stereochemistry: The shape of the molecule matters; one form may work better than the other
(e.g., Thalidomide).
• Isosterism and Bioisosterism: Replacing certain atoms can improve drug effectiveness and
safety.
3. Pharmacokinetics (ADME - How the Body Handles the Drug)
• Absorption: How well the drug enters the blood.
• Distribution: How the drug spreads in the body.
• Metabolism: How the liver changes the drug (activating or breaking it down).
• Excretion: How the drug leaves the body (urine, bile, etc.).
4. Biological Factors
• Receptor Binding: Affects how well the drug works. Strong binding means better activity.
• Enzyme Interactions: Some drugs block enzymes (e.g., Aspirin stops pain enzymes).
• pH of the Body: Affects drug stability and absorption.
5. External Factors
• Diet and Food: Some foods change drug absorption (e.g., grapefruit juice increases drug levels).
• Genetics: People with different genes may process drugs differently.
• Diseases: Liver or kidney problems affect drug breakdown and removal.
Theories of drug activity :
Drug activity refers to how a drug interacts with the body to produce a biological effect. Several theories explain how drugs work at the molecular level. Several theories explain how drugs bind to receptors and initiate their action.
1. Occupancy Theory (Clark and Gaddum)
• The effect of a drug depends on the number of receptors occupied by the drug.
• The drug binds reversibly to receptors, forming a drug-receptor complex that produces a
response.
• The magnitude of the effect is proportional to the number of occupied receptors.
• Limitation: It does not explain why different drugs binding to the same receptor can produce
varying effects.
2. Affinity and Intrinsic Activity Theory
• Drug action involves two steps:
o Affinity – The drug binds to the receptor.
o Intrinsic activity – The drug-receptor complex produces a biological effect.
• Some drugs bind but do not activate the receptor (antagonists), while others activate it strongly
(agonists).
• Example: Acetylcholine and its derivatives show different peak responses due to variations in
intrinsic activity.
3. Rate Theory (Paton)
• The rate of drug binding and unbinding from the receptor determines its effect, not just the
number of occupied receptors.
• Fast binding and release (high association-dissociation rate) result in stronger stimulation.
• Agonists have high interaction frequency, while antagonists bind for a longer time, blocking
receptor activity.
• Limitation: It does not explain why some drugs bind strongly but do not activate the receptor.
4. Induced Fit Theory (Koshland)
• The receptor is flexible, and its shape changes upon drug binding to fit the drug better.
• This conformational change activates or deactivates the receptor.
• Example: Enzymes like hexokinase change shape when binding to glucose.
• Some drugs also change their conformation while approaching the receptor to enhance binding.
Structure-Activity Relationship (SAR) and Quantitative:
• Definition:
SAR is a relationship between the chemical structure of a molecule and its biological
activity.
• This idea was first presented by Crum-Brown and Fraser in 1865.
• By modifying different functional groups in a molecule, scientists can enhance activity, reduce
toxicity, or improve selectivity.
• Example: In sulfa drugs, replacing the amide group affects antibacterial activity.
AIM-
1. The analysis of SAR enables the determination of the chemical group responsible for evoking a
target biological effect in the organism.
2. This allows modification of the effect or the potency of a bioactive compound (typically
a drug) by changing its chemical structure.
3. This method was refined to build mathematical relationships between the chemical
structure and the biological activity, known as quantitative structure–activity
relationships (QSAR). A related term is structure affinity relationship (SAFIR).
4. Structure-activity relationship (SAR) studies aim to identify the specific structural characteristics
of a compound' that are associated with its biological activity (e.g., enzyme inhibitory activity,
antimicrobial activity, toxicity etc.).
Applications of SAR:
• Designing more effective and safer drugs.
• Modifying existing drugs to enhance potency and reduce side effects
• Identifying the active pharmacophore (the essential part of the molecule responsible for
activity).
Structure-Activity Relationship (QSAR)
• QSAR is an advanced version of SAR that uses mathematical models to predict the biological
activity of compounds.
• It correlates structural properties (e.g., molecular weight, hydrophobicity, electronic properties)
with biological effects.
• Used in drug discovery, toxicity prediction, and optimization of lead molecules.
Types of QSAR:
1. 2D-QSAR (Two-Dimensional QSAR)
Uses molecular descriptors like hydrophobicity, electronic effects, and steric factors.
Common methods:
• Hansch Analysis: Relates biological activity to physicochemical properties.
• Free-Wilson Analysis: Studies how structural modifications affect activity.
• Example: Predicting drug potency based on logP (lipophilicity) and electronic properties.
2. 3D-QSAR (Three-Dimensional QSAR)
Considers the three-dimensional shape of molecules and their interactions with biological targets.
Common methods:
• Comparative Molecular Field Analysis (CoMFA) – Uses steric and electrostatic fields.
• Comparative Molecular Similarity Indices Analysis (CoMSIA) – Extends CoMFA by including
hydrophobicity and hydrogen bonding effects.
• Example: Studying how a drug fits into a receptor site and predicting its binding affinity
Hantzsch Equation
The Hantzsch equation is a mathematical expression used in 2D-QSAR (Quantitative Structure-Activity
Relationship) to relate the biological activity of a compound to its physicochemical properties. It is based
on Hansch analysis, which considers parameters like hydrophobicity (log P), electronic effects (σ), and
steric factors (Es).
General Form of the Hantzsch Equation:
log (1/C) = α· π + b·σ + c. Es+d
where,C = Minimum effective concentration of the drug
π (pi) = Hydrophobicity parameter (log P)
σ (sigma) = Electronic effect (Hammett constant)
Es = Steric factor (size of the substituent)
a, b, c, d = Regression coefficients determined by statistical analysis
Significance:
Helps in drug design by predicting biological activity based on molecular properties.
Used in QSAR models to find the best molecular modifications for improving drug potency.
Applicable in lead optimization, toxicity prediction, and understanding structure-activity relationships.
Example Application:
In sulfa drugs, increasing hydrophobicity (π) enhances antibacterial activity, while electronic and steric
factors affect binding to the target enzyme.
Drug-Receptor Mechanism:
A drug-receptor mechanism explains how a drug interacts with a specific receptor in the body to produce an effect. Receptors are proteins found on cell surfaces or inside cells that recognize and bind to drugs. This binding triggers a response, such as pain relief or lowering blood pressure.
Types of Drug-Receptor Interactions
1. Agonists – Activate the receptor and produce an effect.
Example: Morphine activates opioid receptors to reduce pain.
2. Antagonists – Bind to the receptor but block its action.
Example: Naloxone blocks opioid receptors to stop overdose effects.
3. Partial Agonists – Activate receptors but produce a weaker effect than full agonists.
Example: Buprenorphine for pain relief.
1. Inverse Agonists – Bind to the receptor and produce the opposite effect of an agonist.
2. Example: Antihistamines reduce allergy symptoms by blocking histamine receptors.
Theories of Drug-Receptor Mechanism
1. Occupancy Theory – The effect depends on the number of receptors occupied by the drug.
2. Rate Theory – The response depends on how fast the drug binds and unbinds from the receptor.
3. Induced Fit Theory – The receptor changes shape when the drug binds, activating it.
How Drug Effects Are Produced
1. Ion Channel Receptors – Drugs open or close ion channels (e.g., GABA for sedation).
2. G-Protein Coupled Receptors (GPCRs) – Trigger a series of reactions inside the cell (e.g., adrenaline
effects).
3. Enzyme-Linked Receptors – Activate enzymes for cellular responses (e.g., insulin action).
4. Intracellular Receptors – Drugs enter the cell and bind to DNA, affecting gene expression (e.g., steroid
hormones).
Quick summary
In this post, we studied how drugs work in the body by interacting with receptors. A drug produces its effect only when it binds to the correct receptor, just like a key fits into a lock.
We learned that drug activity depends on three main factors:
Hydrophobicity (π) – more lipophilic drugs (like sulfa drugs) usually show better antibacterial action.
Electronic effects – help the drug attach properly to the target enzyme.
Steric effects – decide whether the drug can fit at the binding site or not.
We also understood the drug–receptor mechanism, where receptors (proteins on or inside cells) recognize drugs and produce effects like pain relief, reduced blood pressure, or allergy control.
Different types of drugs act differently:
Agonists activate receptors
Antagonists block receptors
Partial agonists give a weaker response
Inverse agonists produce opposite effects
Finally, we studied important theories (Occupancy, Rate, Induced-fit) and types of receptors (Ion channels, GPCRs, enzyme-linked, intracellular) to understand how drug effects are produced at the cellular level.
👉 If you remember: “Drug + Right Receptor = Effect”, you have remembered this entire topic.
Frequently Asked Questions (FYQs)
1️⃣ What is a drug–receptor mechanism?
A drug–receptor mechanism explains how a drug binds to a specific receptor (protein) in the body to produce a biological effect such as pain relief, sedation, or lowering blood pressure.
2️⃣ What are receptors in pharmacology?
Receptors are proteins present on the cell surface or inside cells that recognize and bind drugs, leading to a physiological response.
3️⃣ What are the types of drug–receptor interactions?
The main types are:
Agonists – activate the receptor
Antagonists – block the receptor
Partial agonists – produce weaker effects
Inverse agonists – produce opposite effects of agonists
4️⃣ What is an agonist? Give an example.
An agonist is a drug that binds to a receptor and produces a response.
Example: Morphine activates opioid receptors to relieve pain.
5️⃣ What is an antagonist? Give an example.
An antagonist binds to a receptor but does not activate it and blocks the action of agonists.
Example: Naloxone blocks opioid receptors during overdose.
6️⃣ What is the difference between agonist and antagonist?
Agonist: Activates receptor and produces effect
Antagonist: Blocks receptor and prevents effect
7️⃣ What are partial agonists?
Partial agonists bind to receptors but produce a lower response than full agonists, even at maximum dose.
Example: Buprenorphine.
8️⃣ What is an inverse agonist?
An inverse agonist binds to the same receptor as an agonist but produces the opposite effect.
Example: Some antihistamines reduce allergic responses.
9️⃣ What are the theories of drug–receptor interaction?
The main theories are:
Occupancy theory
Rate theory
Induced-fit theory
🔟 What is Occupancy Theory?
According to this theory, the drug effect depends on the number of receptors occupied by the drug.
1️⃣1️⃣ What is Induced-fit theory?
This theory states that the receptor changes its shape when the drug binds, leading to activation.
1️⃣2️⃣ What are the types of receptors in the body?
Main types include:
Ion channel receptors
G-protein coupled receptors (GPCRs)
Enzyme-linked receptors
Intracellular receptors
1️⃣3️⃣ How do hydrophobicity and steric factors affect drug activity?
Hydrophobicity (π): Increases drug penetration and activity
Steric factors: Control how well a drug fits at the binding site
Electronic factors: Help in strong binding to enzymes or receptors
1️⃣4️⃣ Why is hydrophobicity important in sulfa drugs?
In sulfa drugs, increased hydrophobicity improves antibacterial activity by enhancing binding to the target enzyme.
1️⃣5️⃣ Why is drug–receptor mechanism important in medicinal chemistry?
It helps in:
Designing safer and effective drugs
Reducing side effects
Understanding drug action at molecular level
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