Library Design Concepts

Hobbs DW, Guo T, Library design concepts and implementation strategies, J. Recept. Signal Transduct. Res., 21 311-356, 2001. 

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. 

Quantitative Structure-Activity Relationship models are used increasingly in chemical data mining and combinatorial library design [5, 6]. For example, three-dimensional (3-D) stereoelectronic pharmacophore based on QSAR modeling was used recently to search the National Cancer Institute Repository of Small Molecules [7] to find new leads for inhibiting HIV type 1 reverse transcriptase at the nonnucleoside binding site [8]. A descriptor pharmacophore concept was introduced by us recently [9] on the basis of variable selection QSAR the descriptor pharmacophore is defined as a subset of... 

The PSSC concept provides a conceptually new principle to inspire compound library design for chemical biology and medicinal chemistry... 

Application of PSSC is not limited to existing crystal structures of proteins. It could be applied to structures derived from homology models as well. A homology model, as applied for the 11 HSD types 1 and 2 enzymes performed well in the first application of PSSC for compound library design. Furthermore, it should be noted that the concept has not been developed to make predictions on structural complementarity or the appropriate orientation of functional groups in the binding site. 

In this chapter, we will give a brief introduction to the basic concepts of chemoinformatics and their relevance to chemical library design. In Section 2, we will describe chemical representation, molecular data, and molecular data mining in computer we will introduce some of the chemoinformatics concepts such as molecular descriptors, chemical space, dimension reduction, similarity and diversity and we will review the most useful methods and applications of chemoinformatics, the quantitative structure-activity relationship (QSAR), the quantitative structure-property relationship (QSPR), multiobjective optimization, and virtual screening. In Section 3, we will outline some of the elements of library design and connect chemoinformatics tools, such as molecular similarity, molecular diversity, and multiple objective optimizations, with designing optimal libraries. Finally, we will put library design into perspective in Section 4. 

Physico-chemical properties and evaluation of potential safety liabilities are important aspects of the library design process. Predicted properties like hERG liability (45), compound aqueous solubility, etc. (46-48) have been extensively studied and included in various library design strategies (49, 50) as a part of multiple constraints optimisation. We have therefore further extended the ProSAR concept to take the library property profile into account in the design process. Several in-house calculated properties are considered these include a compound novelty check (that checks in in-house and external compound databases to see if the compound is novel), predicted aqueous solubility... 

The design of libraries is generally preceded by the selection of some rational catalyst concept, yet may include some degree of serendipity. Library Studio [31] served as the principal library design tool. To design a thin film library, the substrate or destination for the materials array is selected, in this case an 8x8 electrode array, as described above. The set of chemical sources (e.g., metals or metal... 

---