What is Medicinal Chemistry (section 9)

 Section 9: Designing Drugs

Drug designing is the process of creating new medicines based on how a disease works in the body. Scientists try to make a compound that can interact with a specific biological target (like an enzyme or receptor) and cure or control the disease.

Drug design is a combination of chemistry, biology, pharmacology, and computer science. It aims to create drugs that are effective, safe, stable, and easy to take (like oral tablets or injections).

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1. Why is Drug Design Important?

Good drug design helps to:

• Increase effectiveness of treatment
• Reduce side effects
• Target specific tissues or cells
• Improve patient convenience (e.g., once-a-day tablet)

Without drug design, we would depend only on random discoveries or traditional medicines.

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2. Steps in Drug Design

1. Identify the disease
2. Choose the drug target (enzyme, receptor, DNA, etc.)
3. Find lead molecules (from natural sources or chemical libraries)
4. Modify the leads to improve activity and reduce toxicity
5. Test the drug in lab models
6. Develop dosage forms and test in humans

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3. Types of Drug Design

A. Structure-Based Drug Design (SBDD)

This method uses the 3D structure of the target (like a protein or enzyme) to design a drug that fits exactly into it.

Example: Designing HIV protease inhibitors by studying the structure of the HIV enzyme.

B. Ligand-Based Drug Design (LBDD)

Used when the target’s 3D structure is not known. Scientists use known active compounds (ligands) to design new ones.

Example: Designing new antihistamines by modifying older ones.

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4. Lock and Key Model

This is a famous model in drug design:

• The target (like an enzyme) is the “lock.”
• The drug is the “key.”

The drug must fit exactly into the target site to produce the desired effect.

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5. Induced Fit Model

Sometimes, the target changes shape slightly when the drug binds. This is called induced fit, and drug design must consider such flexibility.

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6. Pharmacophore in Drug Design

A pharmacophore is the essential part of a drug molecule responsible for its biological activity.

It includes:

• Hydrogen bond donors/acceptors
• Aromatic rings
• Hydrophobic regions
• Positive/negative charges

Pharmacophore modeling helps in designing new molecules with the same key features.

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7. Optimising Drug-Like Properties

To design a successful drug, scientists improve:

Property	Why It’s Important
Potency	Drug must work in small doses
Selectivity	Should target only diseased cells
Solubility	Must dissolve in body fluids
Absorption	Should enter bloodstream easily
Metabolism	Should not break down too quickly
Toxicity	Should not harm healthy cells
Stability	Should survive during storage and in the body

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8. Lipinski’s Rule of Five

This rule helps in predicting whether a drug will be orally active.

A good oral drug should have:

• Molecular weight < 500
• Log P (fat solubility) < 5
• Hydrogen bond donors ≤ 5
• Hydrogen bond acceptors ≤ 10

Drugs that break more than one rule are likely to have poor absorption.

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9. Tools Used in Drug Designing

Tool	Function
Molecular Modelling	Visualizing drug-target interaction
Docking Software	Simulates drug binding to target
QSAR Models	Predict activity based on structure
Databases (e.g., PubChem)	Provides chemical and biological data
ChemDraw	Used to draw chemical structures
SwissADME, Molinspiration	Predicts drug-likeness and ADME properties

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10. Case Study: Designing Anti-HIV Drugs

• Target: HIV protease enzyme
• Structure: Known from X-ray crystallography
• Strategy: Design a molecule to block the enzyme
• Result: Drugs like saquinavir, ritonavir, indinavir

These drugs stop virus replication and are life-saving for HIV patients.

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11. Challenges in Drug Design

Challenge	Explanation
Drug resistance	Microbes or cancer cells change, drug stops working
Off-target effects	Drug interacts with unintended targets
High development cost	Takes millions of dollars to develop a drug
Regulatory hurdles	Must pass strict safety tests
Bioavailability issues	Drug may not reach required concentration

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12. Prodrugs in Drug Design

A prodrug is an inactive form of a drug that becomes active after entering the body. It is designed to:

• Improve solubility
• Reduce irritation
• Enhance absorption

Example:

• Enalapril → converted to Enalaprilat in the body (active form)

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13. Rational Drug Design vs Random Screening

Rational Drug Design	Random Screening
Based on knowledge of target	Based on trial and error
Faster and more cost-effective	Slower and expensive
Better predictability	Lower chances of success

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14. Green Chemistry in Drug Design

Now scientists try to design drugs using eco-friendly methods:

• Less toxic solvents
• Fewer steps in synthesis
• Renewable raw materials

This is called Green Chemistry, and it supports sustainable drug development.

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15. Summary Table – Drug Design Elements

Element	Purpose
Target Selection	Choose right molecule in the body
Lead Finding	Identify initial compounds
SAR & QSAR	Understand effect of structural changes
Optimization	Improve potency, selectivity, safety
Drug-likeness	Predict oral activity
Docking & Modelling	Simulate interactions in computer

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Conclusion

Drug designing is both an art and a science. By understanding diseases at the molecular level, using computer tools, and applying chemistry principles, scientists can create better, safer, and more effective medicines. In today’s world, where diseases evolve rapidly, drug design helps us stay one step ahead in the fight for health and well-being.