Product-based library design

Product-based approaches can be divided into those that take the combinatorial constraint into account such that each reactant in one pool appears in a product with every reactant from every other reactant pool, and those that merely pick product molecules without consideration of the synthetic constraint. The latter approach is often referred to as cherry-picking and is synthetically inefficient as far as combinatorial synthesis is concerned. In this chapter the emphasis is on product-based library design methods that take the combinatorial constraint into account. 

The rate-limiting step in a product-based library design process is often the calculation cf molecular descriptors. This becomes particularly acute as one moves into the 3D arena, of course, but even the simplest 2D descriptors take a finite time to calculate. In addition, there are the logistics associated with storing virtual libraries of potentially tens of millions of compounds. The ability to search within the possible chemical space of a particular chemistry, as opposed to the limited space of syn-... 

The nature of product-based library design lends itself naturally to the application of heuristic search methods such as simulated annealing and genetic algorithms. Several groups have published applications in the latter area, which has been recently reviewed. While all methods differ somewhat in their technical implementations of the different algorithms, by far the... 

As discussed in this chapter, studies that target natural products using computational methods can be divided into different categories. Although the number is still fairly limited, at least some of the currently available reports introduced important concepts and laid the foundation for natural product-based library design. 

Product-based library design involves a more complex optimization procedure, which we term combinatorial optimization, where the reagent selection is optimized against the properties of the corresponding products. In this scheme, the combinatorial nature of the sublibrary is maintained through combinatorial constraints, while evaluation of diversity, focusing, or other criteria... 

The advent of more accurate and rapid tools in chemoin-formatics and virtual screening makes it possible to design and synthesize a small subset of representative compounds (focused library) of a larger library. Out of various improved methods these two diversity- or structure-based approaches are frequently exercised in the design of a focused library. Once the 3D coordinates of a protein target are determined by either X-ray crystal structures or NMR, a structure-based library design is a more productive and viable approach. 

Natural epothilones have been structurally modified by various teams, making use of the broad stractural scope of natural product-based drag discovery in this field. Generally, this approach includes the de novo construction of libraries of natural product-like compoimds through diversity orientated synthesis (DOS) [17]. A concept for the design of natiual product-based libraries, introduced by H. Waldmann [18], has been developed over the last few years [19] (see also Sects. 1.2.1 and 1.2.2 in the introductory chapter). 

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. 

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