Lead optimization similarity principle

The conceptual basis for similarity analysis is provided by the similarity-property principle that states that similar molecules have similar biological activity.This rather intuitive principle has been widely accepted and substantiated by a wealth of observations. The success of many similarity-based virtual screening calculations can only be rationalized on the basis of this principle. However, minor modifications in molecular structure can dramatically alter the biological activity of a small molecule. This situation is exploited in lead optimization elforts, but limits the potential of similarity methods. These considerations also suggest that there must be fundamental dilferences between the structure-activity relationships (SARs). Thus, difierent types of SARs are expected to critically determine the success of similarity methods and systematic SAR analysis helps to better understand on a case-by-case basis why similarity methods might succeed or fail. 

Many instructive exceptions of the similarity principle were summarized by Kubinyi [48,49]. S ome of these differences could be related to unexpected 3D-bmding modes of ligands in the protein cavity after only minor chemical modifications. These examples show that it is very difficult to describe chemical similarity in an objective and global manner without considering the protein environment. In fact, lead optimization often takes advantage on these surprises and further explores such activity cliffs for biological activity. Regions around early hit structures with a flat SAR are typically less often explored. 

It should be emphasized, that although designs and parameters of the early experimental fast reactors showed a wide variability, those of the commercial-sized plants are rather similar. Even with the initiation of a wholly new line of development, such as Pb and Pb-Bi cooled reactor designs, it is interesting to observe that their parameters are close to those of traditional reactors being advocated elsewhere. It is a further proof that the laws of physics and the principles of good engineering inevitably lead to similar optimal solution. 

A proper kinetic description of a catalytic reaction must not only follow the formation and conversion of individual intermediates, but should also include the fimdamental steps that control the regeneration of the catalyst after each catalytic turnover. Both the catalyst sites and the surface intermediates are part of the catalytic cycle which must turn over in order for the reaction to remain catalytic. The competition between the kinetics for surface reaction and desorption steps leads to the Sabatier principle which indicates that the overall catalytic reaction rate is maximized for an optimal interaction between the substrate molecule and the catalyst surface. At an atomic level, this implies that bonds within the substrate molecule are broken whereas bonds between the substrate and the catalyst are made during the course of reaction. Similarly, as the bonds between the substrate and the surface are broken, bonds within the substrate are formed. The catalyst system regenerates itself through the desorption of products, and the self repair and reorganization of the active site and its environment after each catalytic cycle. 

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