Combinatorial methods definition

Partitioning or cell-based methods provide an absolute measure of the chemical space covered by a collection of compounds. They are based on the definition of a low-dimensional chemistry space, for example, one based on a small number of physicochemical properties such as molecular weight, calculated logP, and number of hydrogen bond donors [45]. Each property defines an axis of the chemistry-space. The range of values for each property is divided into a set of bins, and the combinatorial product of all bins then defines the set of cells or partitions that make up the space. 

The chemical world is often divided into measurers and makers of molecules. This division has deep historic roots, but it artificially impedes taking advantage of both aspects of the chemical sciences. Of key importance to all forms of chemistry are instruments and techniques that allow examination, in space and in time, of the composition and characterization of a chemical system under study. To achieve this end in a practical manner, these instruments will need to multiplex several analytical methods. They will need to meet one or more of the requirements for characterization of the products of combinatorial chemical synthesis, correlation of molecular structure with dynamic processes, high-resolution definition of three-dimensional structures and the dynamics of then-formation, and remote detection and telemetry. 

The second equation, with the third (constant) term discarded, is the standard result [compare Eqs. (5), (6) and (Al)]. However, the first expression appears more natural, and is retained, within the combinatorial derivation it embodies the intuitively reasonable prescription that entropy is best measured relative to the parent distribution (°)( t). This was also an essential ingredient of the projection method, as described in Section n.A, where the prior in the entropy expression was likewise identified with the parent. Retaining the parent as prior also avoids subtleties with the definition of the integrals in Eq. (36) in the case where the phases contain monodisperse components, corresponding to 5-peaks in the density distributions [8]. 

The International Union of Pure and Applied Chemistry (IUPAC, 10) proposed a definition of computational chemistry about 15 years after the term was already well established in the lexicon of chemists A discipline using mathematical methods for the calculation of molecular properties or for the simulation of molecular behavior. It also includes, e.g., synthesis planning, database searching, combinatorial library manipulation. The open-ended second part of this statement reflects the disparate opinions of the IUPAC committee and others who contributed comments. 

The design strategies employed to improve combinatorial chemistry have evolved considerably since the early days of peptide and peptidomimetic libraries. The main concern early was on the availability of suitable synthetic methods that could be applied to the synthesis of libraries of small molecules however, this early obstacle has been intensively addressed and at this point can be considered overcome (for examples of new methodology developed for library production see Ref 21). With the ability in hand to prepare many different types of molecules in a variety of formats, the current challenge is to decide what compounds to make. As a consequence, much attention is now focused on the definition and analysis of chemical diversity. 

A group of researchers in Budapest continued the line of Yoneda [16-21] but avoided the combinatorial explosion of the number of products by the preliminary definition of acceptable reaction products. Thus, the species to be included in the mechanism were fixed a priori, and the program provided the list of reactions. They used the matrix technique of Yoneda for the representation of reactions and species structures, but the number of generated reactions was limited by applying certain restrictions. The most important restriction was that bimolecular reactions were considered only with a maximum of three products. The number of generated reactions was kept low based on reaction complexity and thermochemical considerations. The mechanism obtained was reduced by qualitative and quantitative comparisons with experimental results, including contributions of elementary reactions to measured rates. The method proposed 538 reactions for the liquid phase oxidation of ethylbenzene. The reaction-complexity investigation approved only 272 reactions and the reaction heats were feasible in the cases of 168 reactions. This mechanism was reduced to a 31-step final mechanism. 

In order to overcome the synthesis bottleneck in drug discovery, the concept of preparing many compounds at one time (parallel synthesis) rather than one compound at a time (serial synthesis) was bom. In its simplest form, this distinction constitutes the definition of combinatorial chemistry. The origin of the concept has been ascribed (1) to Furka and others as early as 1982. Early applications of parallel synthesis methods were primarily in the area of peptide library synthesis and have been extensively reviewed (2,3). In the early 1990s, however, application to small drug-like molecules was reported (4) and the explosion in combinatorial chemistry activity began. 

Partitioning or cell-based methods are based on the definition of a relatively small finite number of bins on the axes of a multidimensional property space. The bins are then combined to define a set of cells that cover the whole property space. Partitioning involves the identification of a set of characteristics that are of importance in combinatorial libraries, for example, molecular properties that are... 

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