Molecular shape similarity

It is now possible to analyze macromolecular electron densities at a resolution far exceeding the resolution of current x-ray diffraction and other experimental and macromolecular computational techniques. The MEDLA method presents a new perspective for the analysis of global and local shape, molecular similarity, and complementarity. 

As useful as molecular models are, they are limited in that they only show the location of the atoms and the space they occupy. Another important dimension to molecular structure is its electron distribution. We introduced electrostatic potential maps in Section 1.5 as a way of illustrating charge distribution and will continue to use them throughout the text. Figure 1.6(d) shows the electrostatic potential map of methane. Its overall shape is similar to the volume occupied by the space-filling model. The most electron-rich regions are closer to carbon and the most electron-poor ones are closer to the hydrogens. 

Molecular similarity has also been used directly to model toxicity. Bartlett et al. [63] found that the incidence of cutaneous rash from oral penicillins was a function of shape similarity to benzylpenicillin, and Basak et al. [64] used molecular similarity to model the mutagenicity of aromatic and heteroaromatic amines. 

In more recent years, additional progress and new computational methodologies in macromolecular quantum chemistry have placed further emphasis on studies in transferability. Motivated by studies on molecular similarity [69-115] and electron density representations of molecular shapes [116-130], the transferability, adjustability, and additivity of local density fragments have been analyzed within the framework of an Additive Fuzzy Density Fragmentation (AFDF) approach [114, 131, 132], This AFDF approach, motivated by the early charge assignment approach of Mulliken [1, 2], is the basis of the first technique for the computation of ab initio quality electron densities of macromolecules such as proteins [133-141],... 

SHAPE FUNCTION AS A DESCRIPTOR OF ATOMIC AND MOLECULAR SIMILARITY... 

Because of its utility for describing the chemical properties of systems, the shape function has proved to be very useful for studies of atomic [55-58] and molecular similarity [54,59-61]. For example, the Carbo indicator of molecular similarity is in fact a shape functional [59] ... 

This similarity indicator, in fact, precedes Parr and Bartolotti s introduction of the shape function terminology [59]. In general, it seems that the shape function is preferred to the electron density as a descriptor of molecular similarity whenever one is interested in chemical similarity. Similarity measures that use the electron density will typically predict that fluorine resembles chlorine less than it resembles sodium, oxygen, or neon using the shape function helps one to avoid conflating similarity of electron number with chemical similarity [53,57]. 

Currently, the most exciting work on the shape function is being done in the fields of atomic and molecular similarity. One certainly expects the shape function to continually appear as those fields continue to progress. However, the role of the shape function in those fields is presently incidental the shape function appears, but underlying theory plays no essential role. It would be interesting to develop molecular similarity measures that exploit the insights from the shape-functional pictures of electronic changes. 

Walker, P. D., Maggiora, G. M., Johnson, M. A., Petke, J. D., and Mezey, P. G. (1995) Shape group-analysis of molecular similarity—Shape similarity of 6-membered aromatic ring-systems../. Chem. Inf. Comput. Sci. 35, 568-578. 

Moreover, the shape factor could play an important role when looking at molecular similarity, where the most often used similarity index SI is [32] ... 

Irradiation of lower molecular weight samples in the fluid N phase at 313 or 366 nm led to an unusual result [21]. In the first few seconds of irradiation the perturbed spectrum of the N phase exhibited hyperchromism (an increase in absorbance) and its shape became similar to that of the spectrum of the isotropic melt. This effect is also observed upon triplet sensitization which, like 366-nm irradiation, suppresses photo-Fries rearrangement [28]. It has not yet been proved that this effect is accompanied by a phase change from N to I induced by photoproducts essentially acting as impurities in the mesophase. The effect could be at the microscopic level where formation of a cyclobutane dimer or other photoproduct could interrupt H-type aggregated chromophore stacks, or confor-... 

Apparently, the concept of similarity plays an important role in the chemistry of functional groups. Motivated by the recent revival of interest in molecular similarity [7-39], we shall present a systematic approach towards a quantum chemical description of functional groups. There are two main components of the approach described in this report. The first component is shape-similarity, based on the topological shape groups and topological similarity measures of molecular electron densities[2,19-34], whereas the second component is the Density Domain approach to chemical bonding [4]. The topological Density Domain is a natural basis for a quantum... 

Additional advantages have been pointed out in the Introduction. Since density domains play a major role in molecular shape analysis and in the construction of various molecular similarity measures [5], shape analysis and molecular similarity can be formulated in terms of quantum-chemically defined functional groups. This model is also compatible with a rather general, algebraic-geometrical framework discussed in ref. [6]. 

Mezey, P.G.,"Methods of Molecular Shape-Similarity Analysis and Topological Shape Design". In Dean, P.M., ed., Molecular Similarity in Drug Design (Chapman Hall - Blackie Publishers, Glasgow, U.K., 1995). 

A powerful extension to the potential pharmacophore method has been developed, in which one of the points is forced to contain a special pharmacophore feature, as illustrated in figure 4. All the potential pharmacophores in the pharmacophore key must contain this feature, thus making it possible to reference the pharmacophoric shapes of the molecule relative to the special feature. This gives an internally referenced or relative measure of molecular similarity/diversity. The special feature can be assigned to any atom-type or site-point, or to special dummy atoms, such as those added as centroids of privileged substructures [7, 10]. With one of the points being reserved for this special feature, it would seem even more necessary to use the 4-point definition to capture enough of the... 

R.P. Bywater, Quantitative Measurement of Molecular Similarity Using Shape Descriptors, R. Carbo, Ed. Molecular Similarity and Reactivity From Quantum Chemical to Phenomenological Approaches Kluwer Academic Publ. Dordrecht, The Netherlands, 1995, pp 113-122. 

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