Combinatorial libraries evaluation

Tondi D, Costi MR Enhancing the drug discovery process by integration of structure-based design and combinatorial synthesis. In Viswanadhan AK, Chose VN, editors. Combinatorial library design and evaluation. New York Marcel Dekker, 2001. p. 563-604. 

Darvas F, Dorman G, Papp A. Diversity measures for enhancing ADME admissibility of combinatorial libraries. J Chem Inf Comput Sci 2000 40 314-22. Klopman G, Dimayuga M, Talafous J. META. 1. A program for the evaluation of metabolic transformations of chemicals. J Chem Inf Comput Sci 1994 34 1320-5. 

The next vague of tools will be around computational or in silico ADME approaches. These will allow to include ADME into the design of combinatorial libraries, the evaluation of virtual libraries, as well as in selecting the most promising compounds to go through a battery of in vitro screens, possibly even replacing some of these experimental screens. Several of these computational tools are currently under development as will be discussed in this volume. 

To study the role of lysine residues in susceptibility to formalin fixation, the amino acid composition of immunoreactive peptides (to various monoclonal antibodies) was studied. Each peptide was evaluated to determine if immu-noreactivity was lost after formalin fixation. Formalin sensitivity was correlated with the peptides amino acid composition. The first step in the method is biopanning from a peptide combinatorial library with a monoclonal antibody. The peptides that bind to the antibody were tested for their sensitivity to formalin fixation. Some peptides remain immunoreactive whereas others do not. The peptides were then sequenced to look for differences between those that were sensitive to formaldehyde versus those that were not. The goal was to find whether there is a particular amino acid that is present in formalin-sensitive epitopes but absent in formalin-resistant epitopes, or vice versa. An advantage of this approach is that it is open-ended, without excluding any amino acids. 

Combinatorial libraries have been prepared as discrete compounds or as mixtures with each approach having obvious advantages and disadvantages. Establishing the presence and purity of library members is straightforward when discrete compounds are synthesized. In addition, biological evaluation of discrete compounds directly corre-... 

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. 

Horvath, D. In Combinatorial Library Design and Evaluation. Principles, Software Tools, and Applications in Drug Discovery, Ghose, A.K. and ViSWANADHAN, V.N. (Eds). Marcel Dekker, New York, 2001, 429-472. 

Ghose, A. K. and Viswanadhan, V. N. (eds.) (2001) Combinatorial library design and evaluation principles, software tools and applications in drug discovery. Marcel Dekker, New York. 

While not exactly the same as the methods described above in that DOE cannot be applied retrospectively to diverse datasets, it has been used very successfully to guide the selection and evaluation of compounds from combinatorial libraries (59,60). However, DOE has been successfully applied only in cases where limited libraries of related compounds (e.g., peptides) were being evaluated. The reason for this is intuitively obvious, as one of the assumptions of DOE is that variability in the descriptors is continuous and related to activity over a smooth response surface, so that trends and patterns can be readily identified. With HTS data both of these assumptions are generally not true, as molecules can display discontinuous responses to changing features, and the SAR of even related compounds does not map to a smooth continuous response surface (for example, Fig. 2). 

Yurek, D. A., Branch, D. L., and Kuo, M. S. (2002) Development of a system to evaluate compound identity, purity, and concentration in a single experiment and its application in quality assessment of combinatorial libraries and screening hits. 

Jamois, E. A., Hassan, M., and Waldman, M. (2000) Evaluation of reactant-based and product-based strategies in the design of combinatorial library subsets. 

S Sun, J Headrick, T Staller, M Sepaniak. Evaluation of a capillary electrophoretic method for rapid screening of single-component combinatory libraries. J Microcolumn Sep 10 653-660, 1998. 

Fang LL, Wan M, Pennacchio M, Pan JM. Evaluation of evaporative light-scattering detector for combinatorial library quantitation by reversed phase HPLC. Journal of Combinatorial Chemistry 2, 254-257, 2000. 

We have optimized an eight-way MUX coupled to a TOFMS analyzer to carry out eight-channel parallel LC/UV/MS analysis of combinatorial libraries14 in the past 2 years. This system has not only provided the capacity needed for library analysis, but also enabled simultaneous evaluation of experimental parameters to expedite the method development process. In this chapter, we discuss the optimization of this system and present a high-throughput protocol for combinatorial library analysis. We also compare the eight-channel parallel LC/UV/MS system to a conventional single channel LC/UV/MS system in terms of performance and operation. 

At the same time that combinatorial libraries were examined on solid support, scientists were able to evaluate combinatorial libraries in solution with success.11 14 It was suggested that the attached peptides might give... 

Another use for combinatorial libraries has been the screening of peptides for antimicrobrial properties. In this case, the design of the library is based on antimicrobial peptides found in nature. A combinatorial synthesis is used to find alternative unnatural amino acids expected to mimic the antimicrobial properties.23 Peptide libraries also have been used to find compounds that could bind the lytic peptide mellitin.24 The library was synthesized in solution phase, purified, and evaluated using time-of-flight mass spectrometry (TOF-MS). The sequences determined to bind to mellitin contained hydrophobic pairs. By binding to mellitin, they were able to prevent the cell-surface mellitin interaction. This is an example of a peptide library able to afford compounds that interact with other small peptides without having to find an interacting protein first. 

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