Structure-based library design

Murray et al. described another combination of structure-based and focused combinatorial library design [113], starting with positioning synthetically accessible 

Similar strategies have been implemented for other docking programs. For example, the DOCK approach has been extended [116] by an efficient strategy for docking large virtual combinatorial libraries. For multiple scaffold orientations, all potential fragments are attached to the scaffold, their interactions with the receptor 

Weber et al. also applied a genetic algorithm to a modular reaction scheme, but optimized directly against an experimental enzyme assay as the fitness function, rather than a theoretical QSAR model. In 20 generations of parallel synthesis of 20 Ugi reactions, thrombin inhibition was increased from 1000 fiM to 0.22 iiM. 

It is important to keep in mind the cost of synthesis, screening, and identifying the hits from a large combinatorial library. Thus, the number of optimization steps must be fewer than in traditional medicinal chemistry. Nevertheless, the number of compounds tested can be far greater. Careful experimental design at each optimization step helps one to derive the most benefit from all of the available information. 

In another example of the combination of the two methods, Van Vliet et al. docked just the substituents from a combinatorial synthetic scheme into a receptor structure,then searched a library of potential templates to connect the best scoring fragments in the appropriate geometry. The results were scored based on a combination of the docking quality and connection quality. The final assembled molecules were again docked to verify the procedure. 

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Stahl M. Structure-based library design. In Bohm HJ, Schneider G, editors. Virtual screening for bioactive molecules (Vol. 10 of Mannhold R, Kubinyi H, Timmerman H, editors. Methods and principles in medicinal chemistry). Wein-heim Wiley-VCH, 2000, pp. 229-64. 

Plasmepsin II inhibitor, Ki 2 nM from structure-based library design... 

The integration of combinatorial chemistry, structure-based library design and virtual screening [268, 269] also resulted in successful applications [270, 271]. It ultimately should result in broader SAR information about directionality and physicochemical requirements of acceptable building blocks. This concept is based on feasible scaffolds for exploring protein subsites using parallel or combinatorial synthesis. 

The discovery of novel dihydrofolate reductase inhibitors by structure-based library design based on a 5-(dialkylamino)-2,4-diaminopyrimidine scaffold was reported by Wyss et al. [279] (cf Figure 4.5g). On the basis of a diaminopyrimidine core, a virtual... 

Bohm, H.-J. and Stahl, M. (2000) Structure-based library design molecular modeling merges with combinatorial chemistry. Curr. Opin. Chem. Biol. 4, 283-286. 

Bohm, H.-J. (2001) Progress in structure-based library design. In Rational approaches to drug design Proceedings of the 13th European Symposium on QSAR, Holtje, H.-D. and Sippl, W. (eds.), Prous Science, Barcelona, pp. 367-371. 

Docking Methods for Structure-Based Library Design... 

Key words Structure-based library design, drug discovery, docking, high-throughput screening, combinatorial chemistry. 

Fig. 8.1. Schematic depiction of the seed and grow docking approach for structure-based library design. The programs that use this approach include CombiDOCK and PR0 SELECT.

Structure-Based Library Design in Efficient Discovery of Novel Inhibitors... 

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. 

Structure-Based Library Design in Discovery of HCV NS5B Polymerase Inhibitors 3.4.1. Background... 

Three chapters in Section II focus on the methods and applications of structure-based library design. Chapter 8 reviews the docking methods for structure-based library design. Chapters 9 and 10 contain two detailed protocols illustrating how to apply structure-based library design to the successful optimization of lead matters in the real drug discovery projects. 

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