Other Descriptors

The following descriptors have also been applied for diversity analysis (for recent reviews, see [60,61]). 

Several other interesting 2D [11,79] and 3D [80] descriptors have been successfully applied in the recent literature. 

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Thus, a list of 1 5 descriptors was calculated for these purposes, as described below. The partition coefficient log P (calculated by a method based on the Gho.sc/Crip-pen approach [11]) (see also Chapter X, Section 1.1 in the Handbook) was calculated because it affects the solubility dramatically [17, 18]. All the other descriptors were calculated with the program PETRA (Parameter Estimation for the Treatment of Reactivity Applications) [28. ... 

An alternative to principal components analysis is factor analysis. This is a technique which can identify multicollinearities in the set - these are descriptors which are correlated with a linear combination of two or more other descriptors. Factor analysis is related to (and... 

B and W J Howe 1991. Computer Design of Bioactive Molecules - A Method for Receptor-Based Novo Ligand Design. Proteins Structure, Function and Genetics 11 314-328. i H L 1965. The Generation of a Unique Machine Description for Chemical Structures - A hnique Developed at Chemical Abstracts Service. Journal of Chemical Documentation 5 107-113. J 1995. Computer-aided Estimation of Symthetic Accessibility. PhD thesis. University of Leeds, itan R, N Bauman, J S Dixon and R Venkataraghavan 1987. Topological Torsion A New )lecular Descriptor for SAR Applications. Comparison with Other Descriptors. Journal of emical Information and Computer Science 27 82-85. 

Filimonov DA, Poroikov VV, Borodina Y, Gloriozova T. Chemical similarity assessment through multilevel neighborhoods of atoms definition and comparison with the other descriptors. J Chem Inf Comput Sci 1999 39 666-70. 

Descriptors used to characterize molecules in QSAR studies should be as independent of each other (orthogonal) as possible. When using correlated parameters there is an increased danger of obtaining non-predictive, chance correlation [56]. To examine the correlation between PSA (calculated according to the fragment-based protocol [10]) and other descriptors, we studied a collection of 7010 bioactive molecules from the PubChem database [57]. In addition to PSA, the following parameters were used ... 

H-bonding is an important, but not the sole, interatomic interaction. Thus, total energy is usually calculated as the sum of steric, electrostatic, H-bonding and other components of interatomic interactions. A similar situation holds with QSAR studies of any property (activity) where H-bond parameters are used in combination with other descriptors. For example, five molecular descriptors are applied in the solvation equation of Kamlet-Taft-Abraham excess of molecular refraction (Rj), which models dispersion force interactions arising from the polarizability of n- and n-electrons the solute polarity/polarizability (ir ) due to solute-solvent interactions between bond dipoles and induced dipoles overall or summation H-bond acidity (2a ) overall or summation H-bond basicity (2(3 ) and McGowan volume (VJ [53] ... 

While the shape factor, introduced in the previous section, provides a quantitative definition or description of particle shape, there are other descriptors such as flakiness ratio, flakiness index, elongation index and angularity number which are also found to be in vogue. 

Some simple global descriptors are molecular weight, number of atoms present in a molecule (e.g., number of chlorine atoms), number of double bonds, etc. Other descriptors represent the ramification of the molecule. Certain descriptors take into consideration the electronic charge on a certain atom, or its polarity. 

Over time other descriptors have been investigated in an attempt to better explain certain factors, such as chemical reactivity and molecular size. Nowadays thousands of chemical descriptors can be calculated and thousands of fragments can be obtained using other programs. 

Overall trends in covalent/ionic resonance will be compared with net charge transfer and other descriptors previously correlated with H-bond strength. 

For modeling the BBB penetration, authors used Abraham s data set of 57 compounds as the training set. The test set consisted of 13 compounds, 7 of which were taken from Abraham s data set and 6 from the data set of Lombardo and workers. In addition to the lipoaffinity descriptor, the other descriptors used by them include molecular weight and TPSA. Two models were developed one based on stepwise MLR and the other one based on ANN. To test the performance of different descriptors, they first carried out a simple LR of the 55 training set compounds (two outliers were removed) using TPSA as the only descriptor (Eq. 41). The equation was comparable to Clark s model (Eq. 33). 

Other descriptors are useful for implementing ADMET constraints upon the ligand derivatives. For example, using fhe CMPNTS descriptor, one can limit the number of rotatable bonds fhe derivative wiU possess. The ATYPE descriptor can be used to limit the number of hydrogen bond donors and acceptors that will be included in fhe derivative. Furthermore, fhe MW descriptor can be used to insure that the generated compounds fall within acceptable size limits. 

WOMBAT [39] is a Cabinet database that provides information about biological activity of small molecules [40]. The dataset comes from publications in the Journal of Medicinal Chemistry and other periodicals. WOMBAT is updated twice a year. The data consist of series of compounds that were observed and compared for a specific activity, for example, Ki, IC50, D2 and EC50. The database also includes calculated LogP and Log S values, as well as other descriptors related to flexibility, size, and so on. 

Vectors whose components have continuous values correspond to the more traditional types of vectors found in the physical sciences. They are of identical form to the discrete-valued vectors (see Eq. 2.16) except that the components, vA(xk), are continuous valued. In chemoinformatics, however, the nature of the components is considerably different from those typically found in physics. For example, physiochemical properties, such as logP, solubility, melting point, molecular volume, Hammett ap parameters, and surface charge, as well as other descriptors derived explicitly for the purpose, such as BCUTs... 

The only difference between these two models is the first descriptor. Given the location and disparity between the descriptors, both can be considered false bringing attention to a region that is not important to the model. In Model 2 the descriptor adds to the model, yet in Model 4 the descriptor subtracts from the model. Most striking is that the descriptors are separated by 2.24 A as illustrated in Fig. 10 and more than 6 A from either of the other descriptors at the substitution locations of interest. The two descriptors at positions (0, 2, 4, any) and (0, 4, 1, any) at the me la and para substituent locations of the benzene ring are the most important of those displayed. The descriptors represent steric properties because they will accept any type of heavy atom at those two locations the addition of a heavy atom at either of these two locations will improve the bioactivity of a compound from the series. 

In principle, the integrand in (13.10) might be evaluated with Taylor series expansions such as (12.96), based on successively higher derivatives of the initial state. In practice, however, direct experimental evaluation of the functional dependence of each My on path variables would be needed to evaluate C along extended paths. Further discussion of global curvature or other descriptors of the Riemannian geometry of real substances therefore awaits acquisition of appropriate experimental data, well beyond that required to describe individual points on a reversible path. 

Log P correlated well for six-carbon aromatics and small alcohols and carboxylic acids (in regard to number of carbons). Correlations for two-carbon alkanes were also better than the other descriptors (see Figure 5.15). 

Molecular surface area is one of the other descriptors, which can be derived using molecular modeling techniques forthe estimation of solubility. Theoretically, the dissolution process can be carried out in... 

Pharmacophore definition description of the type of pharmacophore locations and associated functions. Can other descriptors be added to the pharmacophore alignment ... 

Other descriptors provided by MOE [85]) Number of hydrogen bond acceptor atoms Number of hydrogen bond donor atoms... 

Other chemical descriptors have been used to model other properties, or to improve the QSAR models with log P. The attempt has been to avoid the errors of the QSAR models. Indeed, some chemicals were not correctly modeled, and other descriptors have been introduced, producing multilinear relationships. The theoretical assumptions were modeled keeping into account other physico-chemical parameters, such as chemical reactivity, through chemical descriptors, such as the energy of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). 

In explaining the variance in pharmacokinetic parameters, log Poet. is not always a sufficient descriptor. The failure to correlate the kinetics of distribution and the storage of barbiturates in adipose tissue with log Poet. can serve as an example. Again, other descriptors have been investigated [90]. 

VI. Software for the Calculation of Physicochemical Properties and Other Descriptors... 

Table 3.7 A Summary of Packages Used to Calculate Physicochemical Properties and Other Descriptors for QSAR analysis... 

VI. SOFTWARE FOR THE CALCULATION OF PHYSICOCHEMICAL PROPERTIES AND OTHER DESCRIPTORS... 

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