Maximum chemical diversity

Wohnsland and Faller ([175] performed measurements using a thin (9-10 //in) supported, phospholipid-free hexadecane layer. To validate their model, they used 32 well-characterized chemically diverse compounds. The permeability values obtained with their model could be correlated with known human absorption values if the maximum permeability obtained at different pH was taken into account. However, several disadvantages are related to this method. For hydrophilic drugs, hexadecane by itself has an increased barrier function in comparison with membranes. In addition, the hexadecane layers are not very stable, which makes this assay difficult to apply as a routine screening method. The advantage of this PAMPA setup is that it appears to be a satisfactory substitute for obtaining alkane-water partition coefficients, which are usually very difficult to measure directly, due to the poor solubility of drug molecules in alkanes. 

The combination of structure-based design and combinatorial chemistry can facilitate the generation of recombined compounds to rapidly produce potent compounds with maximum chemical and structural diversity. 

Primary libraries are not inspired by any strucmral information, and their purpose is to contain the maximum of chemical diversity so as to function as a potential source of active compounds for many different applications. To consider a library size and its diversity as directly proportional entities is totally wrong, as the simple example in Fig. 5.8 shows. The library on the left, composed of 25 molecules, is much more diverse than the 50-member library on the right because it spans more of the chemical space reported in the figure. While the concept of chemical diversity is intuitive, in order to measure the diversity of library components and to select from them the most representative, we must define some key features and methods. 

The region of chemical space covered by the chemical structures of a screening library must be as large as possible. This implies a maximum of diversity for the structures of the combinatorial library. 

Diversity in chemistry refers to the differences of molecules in a structural aspect, characteristics, or properties. Diversity is a main goal in creating combinatorial compound libraries to achieve maximum chemical, physicochemical, and biological variety (see also Similarity). 

There is a wide range of conversion levels. The term maximum conversion type has no precise definition but is often used to describe a level of conversion, where there is no net fuel oil manufactured. A fuel products refinery with specialities may manufacture lubricating oils, asphalts, greases, solvents, waxes and chemical feed stocks in addition to the primary fuel products. The number and diversity of products will naturally vary from one refinery to another. Refineries produce chemical feed stocks for sale to the chemical affiliates and do not have responsibility for the manufacture of chemical products directly. Both operations may be carried out at the same physical location but the corporate product responsibilities are usually separate. 

A set of n = 209 polycyclic aromatic compounds (PAC) was used in this example. The chemical structures have been drawn manually by a structure editor software approximate 3D-structures including all H-atoms have been made by software Corina (Corina 2004), and software Dragon, version 5.3 (Dragon 2004), has been applied to compute 1630 molecular descriptors. These descriptors cover a great diversity of chemical structures and therefore many descriptors are irrelevant for a selected class of compounds as the PACs in this example. By a simple variable selection, descriptors which are constant or almost constant (all but a maximum of five values constant), and descriptors with a correlation coefficient >0.95 to another descriptor have been eliminated. The resulting m = 467 descriptors have been used as x-variables. The y-variable to be modeled is the Lee retention index (Lee et al. 1979) which is based on the reference values 200, 300, 400, and 500 for the compounds naphthalene, phenanthrene, chrysene, and picene, respectively. 

Because of the importance of carbonyl groups to the mechanism of condensation reactions, much of the assembly of either straight-chain or branched-carbon skeletons takes place between compounds in which the average oxidation state of the carbon atoms is similar to that in carbohydrates (or in formaldehyde, H2CO). The diversity of chemical reactions possible with compounds at this state of oxidation is a maximum, a fact that may explain why carbohydrates and closely related substances are major biosynthetic precursors and why the average state of oxidation of the carbon in... 

In the fine chemicals and pharmaceutical industries, reactors are often used for diverse processes. In such a case, it is difficult to define a scenario for the design of the pressure relief system. Nevertheless, this is required by law in many countries. Thus, a specific approach must be found to solve the problem. One possibility, that is applicable for tempered systems, consists of reversing the approach. Instead of dimensioning the safety valve or bursting disk, one can choose a practicable size and calculate its relief capacity for two-phase flow with commonly-used solvents. This relief capacity will impose a maximum heat release rate for the reaction at the temperature corresponding to the relief pressure. 

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