Pharmacophore generation

Funk OF, Kettmann V, Drimal J, Langer T. Chemical function based pharmacophore generation of endothelin-A selective receptor antagonists. J Med Ghent 2004 47 2750-60. 

Comparative Molecular Field Analysis (CoMFA), 6 16 16 755-757 pharmacophore generation and validation, 6 12 Comparative Molecular Shape Indexes Analysis (CoMSIA), J0 327t,... 

Computing properties, defined, 76 729-730 CoMSIA, pharmacophore generation and validation, 6 12 Concavalin A (Con A), 9 66-67 Concave receptor, 76 774 Concentrate, defined, 76 127 Concentration... 

Barbaro, R., Betti, L., Botta, M., Corelli, F., Giannaccini, G., Maccari, L., Manetti, F., Strappaghetti, G. and Corsano, S. (2001) Synthesis biological evaluation, and pharmacophore generation of new pyridazinone derivatives with affinity toward alpha(l)- and alpha(2)-adrenoceptors. Journal of Medicinal Chemistry, 44, 2118-2132. 

Sippl, W. (2006) in Methods and Principles in Medicinal Chemistry - Pharmacophore Generation and Concepts (eds T. Langer and R. Hofmann) (series eds H. Kubinyi, G. Folkers and R. Mannhold),... 

The generation of the correct compound structures is a critical step in which different components such as atomic valences, correct bond orders and properly defined aromaticity have to be considered carefully. In addition, the correct stereochemistry flags need to be added for a correct treatment of stereochemistry. Most of the current pharmacophore generation packages include compound builders, but users can also import them from external sources using common file formats, for example SMILES, MOL, SD or MOL2. 

There are numerous references in the literature, e.g. [17], showing the effects of various sets of conformational models on pharmacophore generation however, the goal of this chapter is not to describe and analyze the different approaches. 

The validation of the pharmacophore models is therefore a critical aspect of the pharmacophore generation process. A review of the validation methods applicable to the field of pharmacophore generation is described elsewhere in this book [42]. 

Pharmacophore generation engine which type of pharmacophore perception engine is implemented in the program ... 

Another issue that should be addressed briefly is the relationship between size and resolution of a conformational model particularly in terms of coverage of the low-energy regions of the accessible conformational space. The coverage should at any rate be consistent with the precision of the application which uses the conformational model. During three-dimensional pharmacophore generation for database search purposes, the restriction is given by the tolerance of the pharmacophore query. It has been shown in principle that a limited number of... 

Conformational models generated by other programs can be used for pharmacophore generation and in Catalyst databases by importing multiconformer structures stored, e.g., in SD file format. 

Phase is the pharmacophore generation module provided by Schrodinger [82]. Like other modules available from Schrodinger, Phase uses the Maestro interface [83] as the visualization tool. Maestro provides a molecule sketcher and all the common molecular file formats are supported. 

The pharmacophore generation module in Phase generates pharmacophore models using a four to five step procedure described below. 

Most of the above-mentioned pharmacophore generation techniques use a small number of user selected molecules, commonly called a dataset, to derive the pharmacophore models. With the advent of high-throughput methods [103], there was a need to extract pharmacophore information from much larger datasets. 

As opposed to other pharmacophore generation methods that treat the confor-mer expansion and pharmacophore identification phases separately, SCAMPI combines the two searches and lets them depend on each other. Figure 2.2 illustrates the workflow used by SCAMPI. 

Two classical methods are available in THINK to perform the conformational expansion of molecules systematic search and random search. When the systematic search option is used, the use of contacts check avoids high-energy conformations and reduces the overall processing time. The random method uses a random number generator to select the conformations from within the estimated total number of conformations. The implementation of the program does not prohibit identical conformations to be output resulting from symmetry. These conformations are used in the pharmacophore generation and site search modules. 

Inductive logic programming (ILP) is not a pharmacophore generation method by itself, but a subfield of the machine learning approach. In this field, other methods such as hidden Markov models, Bayesian learning, decision trees and logic programs are available. 

A lot of effort has been invested over the past 20 years in the optimization of the different steps of pharmacophore generation molecular editing and 3D representation, combinatorial enumeration, conformational expansion and pharmacophore perception methodologies for small drug-like data sets. However, we note that today there are still some areas with potential for improvement in the field of ligand-based pharmacophore modeling ... 

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