Structure-based combinatorial chemistry

Keywords Site-focused libraries, structure-based combinatorial chemistry, structure-... 

There is an important interplay between structure-based combinatorial chemistry and diversity. By choosing the most diverse set of compounds within those predicted to bind well, more information becomes available about the structural properties required by compounds to bind, which refines and improves the predictions for the next round of synthesis. In addition, if good hits are found, the information can be fed back to find compounds close in diverse space to the hit. 

Combs, A.P., Kapoor, T.M., Feng, S.B., Chen, J.K., Daudesnow, L.F. and Schreiber, S.L. Protein Structure-Based Combinatorial Chemistry Discovery ofNon-Peptide Binding Elements To Src SH3 Domain. J.Am. Chem. Soc., 1996,118,287-288. 

Molecular structure generation. Combinatorial chemistry requires the generation of virtual molecular libraries, usually defined by given reactants and reactions. For this reason we shall describe algorithms for reaction-based structure generation. 

EK Kick, DC Roe, AG Skillman, G Lm, TJ Ewing, Y Sun, ID Kuntz, lA Ellman. Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsm D. Chem Biol 4(4) 297-307, 1997. 

Precisely defined collections of different chemical compounds are denominated as chemical libraries that can be efficiently prepared by methods of combinatorial chemistry. Each chemical compound owes specific structural, steiic, and electronic properties that determine all possible interactions of the small molecule with a given protein or receptor. The molecule s properties are based on the steiic arrangement of functional groups, including the conformations that can be attained by a specific structure. 

Murray CW, Clark DE, Auton TR, Firth MA, Li J, Sykes RA, Waszkowycz B, Westhead DR, Young SC. PRO SELECT combining structure-based drug design and combinatorial chemistry for rapid lead discovery. J Comput Aided Mol Des 1997 11 193-207. 

Salemme FR, Spurlino J, Bone R. Serendipity meets precision the integration of structure-based drug design and combinatorial chemistry for efficient drug discovery. Structure 1997 5 319-324. 

Hence, the implication of combinatorial chemistry for high throughput generation of structurally diverse hydroxamic acids is self-evident. Several solid-phase approaches for their syntheses have been reported,1 7-11 the majority of which are based on the anchoring of iV-hydroxyphthalimide onto an appropriate solid support. After hydrazine-mediated /V-dcprotcction, /V-acylation of the resin-bound hydroxylamine would yield the desired O-anchored hydroxamic acid, which is typically released by acidolysis. 

On the other hand, there is considerable interest to quantify the similarities between different molecules, in particular, in pharmacology [7], For instance, the search for a new drug may include a comparative analysis of an active molecule with a large molecular library by using combinatorial chemistry. A computational comparison based on the similarity of empirical data (structural parameters, molecular surfaces, thermodynamical data, etc.) is often used as a prescreening. Because the DFT reactivity descriptors measure intrinsic properties of a molecular moiety, they are in fact chemical fingerprints of molecules. These descriptors establish a useful scale of similarity between the members of a large molecular family (see in particular Chapter 15) [18-21],... 

In this section, an example will be given in which a (small) library of a new type of cationic lipids was synthesized and screened for TE (63). For synthesis, combinatorial solid phase chemistry was used. All cationic lipids of the example library are structurally based on 3-methylamino-1,2-dihydroxy-propane as the polar, cationic lipid part. As nonpolar lipid part, different hydrocarbon chains are boimd to the amino group of the scaffold and the amino group was further methylated to get constantly cationic-charged lipids. Lipids were synthesized in both configurations and as racemats, and the counterions were varied as well. Table 1 summarizes the structural features of these lipids. 

Fig. 4.1 Virtual screening tools can be categorized by the compound data to be screened (compound collection, combinatorial library, chemistry space) and the query type (structure-based, ligand-based, descriptor-based, pharmacophore-based). The output is always a list of compounds together with a score quantifying the fit to the query.

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. 

Antel, j. Integration of combinatorial chemistry and structure-based drug design. Curr. Opin. Drug Disc. Dev. 1999,... 

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