Combinatorial chemistry

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Combinatorial chemistry involves the rapid synthesis or the computer simulation of a large number of different but structurally related molecules or materials. It is especially common in CADD (Computer aided drug design) and can be done online with web based software, such as molinspiration.

Contents

Introduction

Synthesis of molecules in a combinatorial fashion can quickly lead to large numbers of molecules. For example, a molecule with three points of diversity (R1, R2, and R3) can generate N_{R_1} \times N_{R_2} \times N_{R_3} possible structures, where N_{R_1}, N_{R_2}, and N_{R_3} are the number of different substituents utilized.

Although combinatorial chemistry has only really been taken up by industry since the 1990s, its roots can be seen as far back as the 1960s when a researcher at Rockefeller University, Bruce Merrifield, started investigating the solid-phase synthesis of peptides. Professor Pieczenik, a colleague of Nobel Laureate Merrifield, synthesized the first combinatorial library. US Patent 5,866,363. In the 1980s researcher H. Mario Geysen developed this technique further, creating arrays of different peptides on separate supports, but not a combinatorial library based on random synthesis.

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 (see medicinal chemistry).

In order to handle the vast number of structural possibilities, researchers often create a 'virtual library', a computational enumeration of all possible structures of a given pharmacophore with all available reactants [1]. Such a library can consist of thousands to millions of 'virtual' compounds. The researcher will select a subset of the 'virtual library' for actual synthesis, based upon various calculations and criteria (see ADME, computational chemistry, and QSAR).

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