COMBINATORIAL CHEMISTRY


Introduction- Combinatorial chemistry comprises chemical synthetic methods that make it possible to prepare a large number (tens to thousands or even millions) of compounds in a single process. These compound libraries can be made as mixtures, sets of individual compounds or chemical structures generated by computer software. Combinatorial chemistry can be used for the synthesis of small molecules and for peptides.

Combinatorial chemistry had been invented by Furka Á (Eötvös Loránd University Budapest Hungary) who described the principle of it, the combinatorial synthesis and a deconvolution procedure in a document that was notarized in 1982. The principle of the combinatorial method is: synthesize a multi-component compound mixture (combinatorial library) in a single stepwise procedure and screen it to find drug candidates or other kinds of useful compounds also in a single process. The most important innovation of the combinatorial method is to use mixtures in the synthesis and screening that ensures the high productivity of the process. Motivations that led to the invention had been published in 2002.

In its modern form, combinatorial chemistry has probably had its biggest impact in the pharmaceutical industry. Researchers attempting to optimize the activity profile of a compound create a ‘library’ of many different but related compounds. Advances in robotics have led to an industrial approach to combinatorial synthesis, enabling companies to routinely produce over 100,000 new and unique compounds per year.

By accelerating the process of chemical synthesis, this method is having a profound effect on all branches of chemistry, but especially on drug discovery. Through the rapidly evolving technology of combi-chemistry, it is now possible to produce compound libraries to screen for novel bioactivities. This powerful new technology has begun to help pharmaceutical companies to find new drug candidates quickly, save significant money in preclinical development costs and ultimately change their fundamental approach to drug discovery.

TYPES OF COMBINATORIAL SYNTHESIS:
1. Solid Phase Combinatorial Synthesis:Since Merrifield pioneered solid phase synthesis back in 1963, work, which earns him a Nobel Prize, the subject, has changed radically. Merrifield’s Solid Phase synthesis concept, first developed for biopolymer, has spread in every field where organic synthesis is involved. Many laboratories and companies focused on the development of technologies and chemistry suitable to SPS. This resulted in the spectacular outburst of combinatorial chemistry, which profoundly changed the approach for new drugs, new catalyst or new natural discovery.
The use of solid support for organic synthesis relies on three interconnected requirements:
1) A cross linked, insoluble polymeric material that is inert to the condition of synthesis.
2) Some means of linking the substrate to this solid phase that permits selective cleavage of some or all of the product from the solid support during synthesis for analysis of the extent of reaction(s), and ultimately to give the final product of interest.
3) A chemical protection strategy to allow selective protection and deprotection of reactive groups.

Merrifield developed a series of chemical reactions that can be used to synthesise proteins. The direction of synthesis is opposite to that used in the cell. The intended carboxy terminal amino acid is anchored to a solid support. Then, the next amino acid is coupled to the first one. In order to prevent further chain growth at this point, the amino acid, which is added, has its amino group blocked. After the coupling step, the block is removed from the primary amino group and the coupling reaction is repeated with the next amino acid. The process continues until the peptide or protein is completed. Then, the molecule is cleaved from the solid support and any groups protecting amino acid side chains are removed. Finally, the peptide or protein is purified to remove partial products and products containing errors.

2. Solution Phase Combinatorial Synthesis:-Despite the focus on the use of solid-phase techniques for the synthesis of combinatorial libraries, there have been few examples where libraries have successfully been made and screened in solution. The benefit of preparing libraries on resin beads has been explained as offering advantages in handling, especially where a need to separate excess reagents from the reaction products is attached to the resin. In most of case a simple filtration effects a rapid purification and the product are ready to further synthetic transformation. But it should be remember that using solid phase chemistry brings several disadvantages as well. Clearly the range of chemistry available on solid phase is limited and it is difficult to monitor the progress of reaction when the substrate and product are attached to the solid phase.

Indeed some groups have expressed a preference for solution libraries because there is no prior requirement to develop workable solid phase coupling and linking techniques. The difficulty in purifying large number of compounds without sophisticated automated processes.

UTILITY OF COMBINATORIAL CHEMISTRY:- Combinatorial chemistry has accelerated the development of a whole set of combinatorial tools comprising combinatorial library design, efficient synthetic methods, reagents for library synthesis (including solid supported reagents), linkers, bilayer beads, library encoding and decoding strategies, HTS methods and equipment, etc. The large diversity combinatorial bead and planar microarrays in the early 1990’s had inspired investigators in fields beyond chemistry to think “combinatorially”; this change in thinking led to the development of oligonuleotide bead and planar microarrays, genomics and many other “-omics” technologies that involve the concurrent interrogation of thousands to hundreds of thousands of analytes or biomolecules.

Although the initial high expectations of combinatorial chemistry for drug discovery have yet to be realized, much has been learned over the last 30 years. Many new chemical, biological, computational, and screening tools have been developed. The limitations and strengths of combinatorial chemistry are better understood. We are now in a better position to truly leverage the power of combinatorial technologies for the discovery and development of next-generation drugs. The future of utilizing combinatorial chemistry for drug discovery is bright.

Mr. Saurabh Chaturvedi, Assistant Professor, School of Pharmacy, Career Point University, Kota

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