Structure-based searches, approaches

It is important that a distinction be made between chemical formulae and chemical structures. For databases with any type of diversity to be realized, the chemical formula cannot provide effective retrieval of compounds. Structure-based searches can take three different approaches ... 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Figure 15.2 Historical progress of ligand structure-based approaches from substructure search to analysis of 3-dimensional molecular interaction fields.

Varady J, Wu X, Fang X, Min J, Hu Z, Levant B, Wang S. Molecular modeling of the three-dimensional structure of dopamine 3 (D3) subtype receptor discovery of novel and potent D3 ligands through a hybrid pharmacophore-and structure-based database searching approach. / Med Chem 2003 46 4377-92. 

Iwata Y, Arisawa M, Hamada R, Kita Y, Mizutani MY, Tomioka N, Itai A, Miyamoto S. Discovery of novel aldose reductase inhibitors using a protein structure-based approach 3D-database search followed by design and synthesis. J Med Chem 2001 44 1718-28. 

J., Zheng, W. (2008) Novel approach to structure-based pharmacophore search using computational geometry and shape matching techniques. / Chem Inf Model 48, 889-901. 

The computational study of the osmium dihydroxylation of aliphatic al-kenes is much more complicated than the case of aromatic alkenes due to the large number of conformations that the former could adopt. To overcome this issue, we considered the system to be composed of two different parts the catalyst and the olefin. For the catalyst, the conformation considered is that from the X-ray structure. As already shown in the study of styrene [95], and in some experimental works [98], the catalyst is a fairly rigid molecule. For the aliphatic alkenes under study, there is a large number of possible conformations in addition, the stability of an olefin conformation is also affected by the interactions between the olefin substituent and the catalyst. Therefore, the catalyst must be included in the conformational search. The conformational analysis was done using a scheme based on the systematic search approach [99]. The strategy consisted of two parts first we developed a method to identify all of the possible conformations afterwards, we screened all of the possible conformations at MM level to select the most stable. Finally, we only carried out the relatively expensive QM/MM calculations on these selected conformations. 

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