Title 3. COMBINATORIAL CHEMISTRY.pdf ✅

PHARMD GURU Page 1 INTRODUCTION:  Combinatorial chemistry is a technique by which large numbers of different but structurally similar molecules are produced rapidly and submitted for pharmacological assay.  This technique uses the same reaction conditions with the same reaction vessels to produce a large range of analogues.  Technique invented in the late 1980s and early 1990s to enable tasks to be applied to many molecules simultaneously. ROLE OF COMBINATORIAL CHEMISTRY - DRUG DISCOVERY PROCESS:  Applications of combinatorial chemistry are very wide Scientists use combinatorial chemistry to create large populations of molecules that can be screened efficiently.  By producing larger, more diverse compound libraries, companies increase the probability that they will find novel compounds of significant therapeutic and commercial value.  Provides a stimulus for robot-controlled and immobilization strategies that allow high-throughput and multiple parallel approaches to drug discovery. ADVANTAGES:  Fast: Combinatorial approach can give rise to million of compound in same time as it will take to produce one compound by traditional method of synthesis.  Economical: A negative result of mixture saves the effort of synthesis, purification & identification of each compound.  Easy: Isolation purification & identification of active molecule from combinatorial library is relatively easy.  Drug Discovery: Mixed Combinatorial synthesis produces chemical pool. Probability of finding a molecule in a random screening process is proportional to the number of molecules subjected to the screening process.  Drug Optimization: Parallel synthesis produces analogues with slight differences which is required for lead optimization. COMBINATORIAL CHEMISTRY

PHARMD GURU Page 3 COMBINATORIAL CHEMISTRY WITHIN DRUG DESIGN:  Combinatorial chemistry can impact at lead discovery.  Traditionally lead drugs were found from:  Natural products.  Synthetic custom crafted organic molecules made in small numbers.  Analogues of known actives (analogue me-toos).  High throughput screening (HTS) requires large numbers of compounds to fuel the discovery process.  As an alternative to traditional synthesis many compounds rapidly constructed was needed. TECHNIQUES USED IN THE COMBINATORIAL SYNTHESIS: THERAPEUTIC TARGET LEAD DISCOVERY LEAD OPTIMISATION DEVELOPMENT CANDIDATE DRUG COMBINATORIAL CHEMISTRY CAN IMPACT HERE. SOLID PHASE TECHNIQUE Solid Support Method. Parallel Synthesis. Mixed Combinatorial Synthesis. Mixed & split combinatorial Synthesis. SOLUTION PHASE TECHNIQUE
PHARMD GURU Page 4 SOLID PHASE SYNTHESIS: Definition: Reactants are bound to a polymeric surface and modified whilst still attached. The final product is released at the end of the synthesis. ADVANTAGES:  Specific reactants can be bound to specific bends.  Beads can be mixed and reacted in the same reaction vessel.  Products formed are distinctive for each bead and physically distinct.  Excess reagents can be used to drive reactions to completion.  Excess reagents and by-products are easily removed.  Reaction intermediates are attached to beads and do not need to be isolated and purified.  Individual beads can be separated to isolate individual products.  Polymeric support can be regenerated and re-used after cleaving the product.  Automation is possible. REQUIREMENTS: 1. Solid support 2. An anchor or linker 3. Protecting groups 1. SOLID SUPPORT: A resin bead or a functionalized surface acts as a solid support. a) POLYSTYRENE RESINS:  Polystyrene resins in this case are cross-linked with divinyl benzene (about 1% cross-linking).  Suitable for nonpolar solvents.  Partially cross-linked polystyrene beads (hydrophobic in nature) cause problems in peptide synthesis due to peptide folding.