Scaffolded combinatorial library

Lee, M.L. Schneider, G. (2001) Scaffold Architecture and Pharmacophoric Properties of Natural Products and Trade Drugs Application in the Design of Natural Product-Based Combinatorial Libraries. Journal of Combinatorial Chemistry, 3, 284-289. 

Fig. 21 Synthetic scheme of benzimidazolium scaffold-based combinatorial library and their general structures and photophysical properties of the representative examples. All the photophysical properties were measured in methanol...

Fig. 18.3 Variation-based strategies. Left The SHAPES Linking Library [11] consists of drug-like scaffolds connected by linkers that are amenable to combinatorial chemistry (dashed line). Hits are followed up by synthesizing a combinatorial library in which the scaffolds are systematically varied. Center Directed Combinatorial Librari es [12] are comprised of scaffolds containing multiple sites for substituents. Hits are followed up by...

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

Nielsen, M. C. Ulven, T. Selective extraction of G-quadruplex ligands from a rationally designed scaffold-based dynamic combinatorial library. Chem. Ear. J. 2008,14, 9487-9490. 

Lee ML, Schneider GJ. (2001) Scaffold architecture and pharmaco-phoric properties of natural products and trade drugs Application in the design of natural product-based combinatorial libraries. Comb Chem 3 284-289. 

Having validated the inverse screening approach for fom unrelated ligands, a prospective screening was carried out to identify the putative targets for representative compounds of a scaffold-focused combinatorial library (Fig. 11). 

Bohl M, Dunbar JB, Gifford EM, Heritage T, Wild DJ, Willett P, Wilton DJ. (2002) Scaffold Searching Automated Identification of Similar Ring Systems for the Design of Combinatorial Libraries. Quant. Struct.-Act. Rel. 21 590-597. 

Grabowski, ., Baringhaus, . -H., Schneider, G. (2008) Scaffold diversity of natural products inspiration for combinatorial library design. Nat Prod Rep 25, 892-904. 

Fragment-based design, where the constituents of the compounds (scaffolds and functional groups/substituents) are docked in the binding site and then linked together to build combinatorial libraries. 

CombiDock Tweaks the DOCK algorithm to identify suitable scaffold orientations in the binding pocket. Proceeds using the seed and grow approach to design combinatorial libraries (73)... 

Stahura, F. L., Xue, L., Godden, J. W., Bajorath, J. (1999) Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. /Mol Graph Model 17, 1-9, 51-52. 

Generation of a virtual combinatorial library by finding substituents of a custom scaffold that can be accommodated in the binding site of a molecular target or meet other 3D structural criteria. Once the virtual library is synthesized in the computer, individual members can be selected using structural or additional criteria and synthesized using automated equipment. 

As mentioned in the introduction, typically one of the most time-consuming steps in the synthesis of a combinatorial library by solid-phase methods is demonstrating the feasibility and generality of the synthesis of a particular core structure on resin. Hence a strategy wherein the synthetic transformations, once developed and optimized, can subsequently be reused in different contexts to produce an array of different compound classes has considerable merit. Having initially invested a considerable amount of time in establishing the practicability of the first scaffold chemistry (the ben-... 

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