Combinatorial chemistry in drug discovery

Abstract

Several combinatorial methods have been developed to create focused or diverse chemical libraries with a wide range of linear or macrocyclic chemical molecules: peptides, non-peptide oligomers, peptidomimetics, small-molecules, and natural product-like organic molecules. Each combinatorial approach has its own unique high-throughput screening and encoding strategy. In this article, we provide a brief overview of combinatorial chemistry in drug discovery with emphasis on recently developed new technologies for design, synthesis, screening and decoding of combinatorial library. Examples of successful application of combinatorial chemistry in hit discovery and lead optimization are given. The limitations and strengths of combinatorial chemistry are also briefly discussed. We are now in a better position to truly leverage the power of combinatorial technologies for the discovery and development of next-generation drugs.

DNA‐encoded chemical libraries – achievements and remaining challenges

“…The most commonly used strategy for encoding singlepharmacophore libraries is called "DNA-recorded synthesis" and relies on the use of split-and-pool procedures ( Fig. 2A,B) [29,30]. The basic concept behind this technology relates to the synthesis of chemical compounds using multiple steps, each of which is "recorded" by the addition of a DNA fragment that uniquely identifies a given chemical transformation.…”

“…2A,B) [29,30]. The basic concept behind this technology relates to the synthesis of chemical compounds using multiple steps, each of which is "recorded" by the addition of a DNA fragment that uniquely identifies a given chemical transformation.…”

An overview of techniques for multifold enhancement in solubility of poorly soluble drugs

“…Combinatorial chemistry and high throughput screening techniques have been employed by pharmaceutical industries to hasten their drug discovery and development processes [1,2]. These techniques have enabled to synthesize and test a very huge number of compounds per day.…”

Diversity‐Oriented Synthesis of Furo[3,2‐c]coumarins and Benzofuranyl Chromenones through Chemoselective Acylation/Wittig Reaction

“…[4] Benzofuranyl coumarins are another class of coumarins that are known to possess remarkable therapeutic activities,s uch as antibacterial, antianalgesic,a nd even anticancer properties. [6] Earlier,wereported ageneral method for the preparation of an ew type of highly functional phosphorus zwitterions through at andem three-component reaction of functional alkanes,a ldehydes,a nd Bu 3 Pa nd demonstrated the use of these phosphorus zwitterions in the efficient synthesis of furo [3,2-c]coumarins (Scheme 1a). [6] Earlier,wereported ageneral method for the preparation of an ew type of highly functional phosphorus zwitterions through at andem three-component reaction of functional alkanes,a ldehydes,a nd Bu 3 Pa nd demonstrated the use of these phosphorus zwitterions in the efficient synthesis of furo [3,2-c]coumarins (Scheme 1a).…”

“…[5] In view of the therapeutic significance of these two species and the fact that the range of heterocyclic libraries is narrowly defined, the development of efficient and concise synthetic methods that fill the chemical space with diverse heterocyclic structures remains an important task in modern organic chemistry. [6] Earlier,wereported ageneral method for the preparation of an ew type of highly functional phosphorus zwitterions through at andem three-component reaction of functional alkanes,a ldehydes,a nd Bu 3 Pa nd demonstrated the use of these phosphorus zwitterions in the efficient synthesis of furo [3,2-c]coumarins (Scheme 1a). [7] In continuation of our quest towards the chemoselective synthesis of formal crosscoupling adducts and heteroaromatic compounds through Wittig reactions, [8,9] we conceived that the presence of an appropriately positioned hydroxy group on these zwitterions could render two different electrophilic sites after the initial acylation and thus present us with ag reat chance to study ac hemoselective intramolecular Wittig reaction to furnish diverse coumarin skeletons (Scheme 1b).…”