Chemistry descriptors

Similarities between a shape descriptor and a chemistry descriptor may be combined to calculate the final similarity sim(m) for a match m of nodes representing two building blocks. 

MODEL Molecular Descriptor Lab (MODEL) (http //jing.cz3.nus.edu.sg/ cgi-bin/model/model.cgi) is a free Web-based server for computing a comprehensive set of 3778 molecular descriptors, which can be divided into 6 classes constitutional descriptors, electronic descriptors, physical chemistry properties, topological indexes, geometrical molecular descriptors, and quantum chemistry descriptors [73], Compounds can be provided to the server in various molecular formats such as PDB, MDL, MOL2, and COR, and the computed molecular descriptors are displayed in a few seconds or less. Cross-links to the relevant sections of the reference manual page are also provided for some of the descriptors and descriptor classes. 

Many different descriptors have been developed in an attempt to define chemistry spaces that are relevant for bioactivity. Aside from being relevant to biological activity, to be useful for combinatorial chemistry, descriptors should also be relatively easy to calculate in order that the methods can be applied to large datasets. Some descriptors commonly used in virtual screening are described below. For more detail on descriptors, see the chapter by Downs and Barnard and the earlier review by Brown [9]. The most commonly used similarity coefficients are the Tanimoto coefficient and Euclidean distance [10]. A weighting scheme may also be applied to assign relative weights to different descriptors. 

Mixtures containing up to several thousand distinct chemical entities are often synthesized and tested in mix-and-split combinatorial chemistry. The descriptor representation of a mixture may be approximated as the descriptor average of its individual component molecules, e.g., using atom-pair and topological torsion descriptors. 

Steinhauer and Gasteiger [30] developed a new 3D descriptor based on the idea of radial distribution functions (RDFs), which is well known in physics and physico-chemistry in general and in X-ray diffraction in particular [31], The radial distribution function code (RDF code) is closely related to the 3D-MoRSE code. The RDF code is calculated by Eq. (25), where/is a scaling factor, N is the number of atoms in the molecule, p/ and pj are properties of the atoms i and/ B is a smoothing parameter, and Tij is the distance between the atoms i and j g(r) is usually calculated at a number of discrete points within defined intervals [32, 33]. 

R. Todeschini, V Consormi, Handbook of Molecular Descriptors, in Methods and Principles in Medicinal Chemistry, Vol. 11, R. Mannhold, H. Kubinyi, H. Timmerman (eds.), Wiley-VCH, Weinheim, 2000. 

GAs or other methods from evolutionary computation are applied in various fields of chemistry Its tasks include the geometry optimization of conformations of small molecules, the elaboration of models for the prediction of properties or biological activities, the design of molecules de novo, the analysis of the interaction of proteins and their ligands, or the selection of descriptors [18]. The last application is explained briefly in Section 9.7.6. 

The investigation of molecular structures and of their properties is one of the most fascinating topics in chemistry. Chemistry has a language of its own for molecular structures which has been developed from the first alchemy experiments to modem times. With the improvement of computational methods for chemical information processing, several descriptors for the handling of molecular information have been developed and used in a wide range of applications. 

The term fine chemicals is widely used (abused ) as a descriptor for an enormous array of chemicals produced at small scale and is frequently assumed to infer a significant added value of the product derived from the degree of complexity (number of functional groups, geometric isomers, and enantiomers) and precision in their manufacture. Whether the term fine chemicals refers to the finesse of the chemistry or to the small scale of manufacture is far from clear. However, in order to assist our discussion the following division can be adopted [2] ... 

Our approach is to examine small, closely-related series of nitrosamines and to develop structure-activity models based on molecular descriptors which are explicitly meaningful with respect to the organic chemistry and biochemistry of the compounds. The forms of these models can then often be interpreted in terms of the mechanisms through which these compounds exert their carcinogenic effects. 

The concept of property space, which was coined to quanhtahvely describe the phenomena in social sciences [11, 12], has found many appUcahons in computational chemistry to characterize chemical space, i.e. the range in structure and properhes covered by a large collechon of different compounds [13]. The usual methods to approach a quantitahve descriphon of chemical space is first to calculate a number of molecular descriptors for each compound and then to use multivariate analyses such as principal component analysis (PCA) to build a multidimensional hyperspace where each compound is characterized by a single set of coordinates. 

Voelkel, A. Structural descriptors in organic chemistry - new topological parameter based on electrotopological state of graph vertices. Comput. Chem. 1994, 18, 1. ... 

The solubility of chemicals, drugs or pollutants in water (S ), in octanol (S ), their saturation concentration in air Qii), as well as their partitioning in the corresponding two-phase systems [octanol-water (P /w = Q/Cw), air-water (Pair/w = C IC ) and air-octanol (Paij/ = C /Co)] are important physicochemical parameters in medicinal chemistry and in environmental research. The following correlahons of those properties with HYBOT descriptors have been published recently [54—58] ... 

Of course, class 4 is not valuable in medicinal chemistry. Such compounds have to be excluded from drug discovery processes as early as possible. At present, there are computer alert programs based on the Rule-of-5 or similar approaches that are used in preliminary screening to select and exclude compounds of class 4 [71]. Van de Waterbeemd indicated in 1998 that the four BCS classes of drugs can be determined solely by considering physicochemical descriptors such as molecular weight and PSA [72]. However, as mentioned in this chapter, those descriptors are too crude for the quantitative description of molecular size and H-bonding ability. 

A comparahve analysis of coefficients and descriptors clarifies the relationship between lipophilicity and hydrophobicity (Y in Eq. 4 is the molar volume which assesses the solute s capacity to elicit nonpolar interactions (i.e. hydrophobic forces) which, as also clearly stated in the International Union of Pure and Applied Chemistry definitions [3] are not synonyms but, when only neutral species are concerned, may be considered as interchangeable. In the majority of partitioning systems, the lipophilicity is chiefly due to the hydrophobicity, as is clearly indicated by the finding that the product of numerical values of the descriptors V and of the coefficient v is larger in absolute value than the corresponding product of other couples of descriptors/coefficients [9]. This explains the very common linear rela-... 

Klamt, A., Eckert, F. COSMO-RS a novel way from quanmm chemistry to free energy, solubility and general QSAR-descriptors for partitioning. In Rational Approaches to Drug Design, Holtje, H.-D., Sippl, W. (eds.), Prous, Barcelona, 2001, pp. 195-205. 

There are some chemometric (chemometrics is a statistical area which combines statistics and chemistry) tools which use the chemical descriptors and/or fragments of the chemicals used to build up the model, and compare if the chemical descriptors and/or fragments of the target chemical are similar. An example of this approach is given by the freely available software AMBIT. A major disadvantage of this approach is that it is based only on the chemical information. 

Pastor, M., Cruciani, G., McLay, I., Pickett, S. and Clementi, S. (2000). GRid-INdependent descriptors (GRIND) a novel class of alignment-independent three-dimensional molecular descriptors Journal ofMedicnal Chemistry 43 3233-3243. 

Dearden, J. C. (1990) Physico-chemical descriptors. In Practical Applications of Quantitative Structure-Activity Relationships (QSAR) in Environmental Chemistry and Toxicology. Karcher, W. and Devillers, J., Eds., pp. 25-60. Kluwer Academic Publisher, Dordrecht, The Netherlands. 

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