Privileged Structures

1. Introduction to Privileged Structures

• Definition: Privileged structures are molecular frameworks or scaffolds that are capable of binding to multiple biological targets, often with high affinity. These structures are versatile templates in drug discovery.
• Historical Context: The term was first coined by Benjamin Evans in 1988 when studying scaffolds that appeared in multiple biologically active compounds.
• Importance in Medicinal Chemistry:
  • Provide a starting point for drug discovery.
  • Increase efficiency by targeting a wide range of receptors.
  • Often lead to improved hit rates in screening libraries.

2. Characteristics of Privileged Structures

• Common features:
  • High chemical stability.
  • Amenable to functionalization for derivatization.
  • Compatibility with biological environments (e.g., good pharmacokinetics).
• Structural diversity allows them to be adapted to various pharmacophores.
• Often found in natural products or inspired by natural scaffolds.

3. Examples of Privileged Structures

a. Benzodiazepines

• Importance: Bind to GABA-A receptors and are used as anxiolytics, sedatives, and anticonvulsants.
• Versatility: Substitutions on the benzodiazepine scaffold can modify selectivity and activity.
  
  
  

b. Diaryl Ethers

• Example: Combretastatin A-4, a natural product-derived scaffold, shows anticancer activity by inhibiting tubulin polymerization.
• Applications: Broad-spectrum anticancer agents.
  

c. Beta-Lactams

• Importance: Found in penicillins and cephalosporins, essential for antibacterial activity.
• Relevance: Their four-membered ring scaffold is highly reactive, making them effective inhibitors of bacterial cell wall synthesis.
  
  Penicillin Core
  
  Imipenem - antibiotic belonging to the carbapenems.

d. Indole

• Importance: Present in many drugs, such as serotonin receptor agonists and kinase inhibitors.
• Examples: Sumatriptan (migraine treatment) and Zafirlukast (asthma treatment).
  
  Sumatriptan
  
  Zafirlukast

e. Piperazine

• Importance: Common in central nervous system (CNS) drugs, antiparasitic agents, and antibiotics.
• Examples: Ciprofloxacin and Sildenafil.
  
  Ciprofloxacin

f. Purines

• Importance: Found in drugs targeting nucleic acid synthesis and kinases.
• Examples: Adenosine analogs and cancer therapeutics like 6-mercaptopurine.
  

4. Application in Drug Discovery

• Hit-to-Lead Optimization: Privileged structures serve as core scaffolds for designing libraries of compounds.
• Fragment-Based Drug Design (FBDD): Incorporation of these structures helps identify new binding interactions.
• SAR Studies: Structure-activity relationships (SAR) on privileged scaffolds enable fine-tuning for specific targets.

5. Challenges with Privileged Structures

• Risk of redundancy in screening libraries.
• Off-target effects due to the broad target affinity.
• Potential for toxicity if not carefully optimized.