Representation molecular structure methods

The most well-known and at the same time the earliest computer model for a molecular structure representation is a wire frame model (Figure 2-123a). This model is also known under other names such as line model or Drciding model [199]. It shows the individual bonds and the angles formed between these bonds. The bonds of a molecule are represented by colored vector lines and the color is derived from the atom type definition. This simple method does not display atoms, but atom positions can be derived from the end and branching points of the wire frame model. In addition, the bond orders between two atoms can be expressed by the number of lines. 

A proper representation of the molecular structure is crucial for the prediction of spectra. Fragment-based methods, topological descriptors, physicochemical descriptors, and 3D descriptors have been used for this endeavor. 

In the quantum mechanical continuum model, the solute is embedded in a cavity while the solvent, treated as a continuous medium having the same dielectric constant as the bulk liquid, is incorporated in the solute Hamiltonian as a perturbation. In this reaction field approach, which has its origin in Onsager s work, the bulk medium is polarized by the solute molecules and subsequently back-polarizes the solute, etc. The continuum approach has been criticized for its neglect of the molecular structure of the solvent. Also, the higher-order moments of the charge distribution, which in general are not included in the calculations, may have important effects on the results. Another important limitation of the early implementations of this method was the lack of a realistic representation of the cavity form and size in relation to the shape of the solute. 

Since rigorous theoretical treatments of molecular structure have become more and more common in recent years, there exists a definite need for simple connections between such treatments and traditional chemical concepts. One approach to this problem which has proved useful is the method of localized orbitals. It yields a clear picture of a molecule in terms of bonds and lone pairs and is particularly well suited for comparing the electronic structures of different molecules. So far, it has been applied mainly within the closed-shell Hartree-Fock approximation, but it is our feeling that, in the future, localized representations will find more and more widespread use, including applications to wavefunctions other than the closed-shell Hartree-Fock functions. 

Chemoinformatics refers to the systems and scientific methods used to store, retrieve, and analyze the immense amount of molecular data that are generated in modern drug-discovery efforts. In general, these data fall into one of four categories structural, numerical, annotation/text, and graphical. However, it is fair to say that the molecular structure data are the most unique aspect that differentiate chemoinformatics from other database applications (1). Molecular structure refers to the 1-, 2-, or 3-D representations of molecules. Examples of numerical data include biological activity, p/C, log/5, or analytical results, to name a few. Annotation includes information such as experimental notes that are associated with a structure or data point. Finally, any structure... 

In this chapter, we will give a brief introduction to the basic concepts of chemoinformatics and their relevance to chemical library design. In Section 2, we will describe chemical representation, molecular data, and molecular data mining in computer we will introduce some of the chemoinformatics concepts such as molecular descriptors, chemical space, dimension reduction, similarity and diversity and we will review the most useful methods and applications of chemoinformatics, the quantitative structure-activity relationship (QSAR), the quantitative structure-property relationship (QSPR), multiobjective optimization, and virtual screening. In Section 3, we will outline some of the elements of library design and connect chemoinformatics tools, such as molecular similarity, molecular diversity, and multiple objective optimizations, with designing optimal libraries. Finally, we will put library design into perspective in Section 4. 

In applying the methods of group theory to problems related to molecular structure or dynamics, the procedure that is followed usually involves deriving a reducible representation for the phenomenon of interest, such as molecular vibration, and then decomposing it into its irreducible components. (A reducible representation will always be a sum of irreducible ones.) Although the decomposition can sometimes be accomplished by inspection, for the more general case, the following reduction... 

Figure 4.1 Ligand-based virtual screening methods. The figure shows different computational methods for screening compound databases that take either a local or a global view on molecular structure. Molecular similarity methods that operate on molecular descriptors, histogram representations, superposition or (reduced) molecular graphs evaluate molecular structure globally. By contrast, local structural features are explored by substructure and pharmacophore searching or QSAR modeling.

A general equation can be derived that describes the variation in direction of the valence electron density about the nucleus. The distortion from sphericity caused by valence electrons and lone-pair electrons is approximated by this equation, which includes a population parameter, a radial size function, and a spherical harmonic function, equivalent to various lobes (multipoles). In the analysis the core electron density of each atom is assigned a fixed quantity. For example, carbon has 2 core electrons and 4 valence electrons. Hydrogen has no core electrons but 1 valence electron. Experimental X-ray diffraction data are used to deri e the parameters that correspond to this function. The model is now more complicated, but gives a better representation of the true electron density (or so we would like to think). This method is useful for showing lone pair directionalities, and bent bonds in strained molecules. Since a larger number of diffraction data are included, the geometry of the molecular structure is probably better determined. 

The concept of orbital hybridization deserves a few summary comments. The method is used throughout basic and applied chemistry to give quick and convenient representations of molecular structure. The method provides a sound quantum mechanical basis for organizing and correlating vast amounts of experimental data for molecular structure. The simple examples discussed earlier all involved... 

Among the computational methods available, QSARs, or more general, quantitative structure-property relationships (QSPR) have been widely used not only in drug design and environmental chemistry but also in food-related studies. QSPR studies are grounded in the concept that a property (e.g., biological activity, reactivity, toxicity, volatility, etc.) depends on the molecular structure and that is possible to find a mathematical or quantitative relationship between that property and a suitable molecular representation (e.g., some combination of descriptors). 

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