Congeneric drugs

So far we have taken into account only the steric and electrostatic fit of congeneric drug molecules that bind at the same receptor site. This is clearly not sufficient if one aims towards a more detailed description of the structural properties of a receptor. Besides the already mentioned characteristics, hydrophobic areas, regions of charge transfer or several types of different polar interactions can also be distinguished. A receptor map which contains three-dimensional information of this kind is very helpful in the interpretation and understanding of known experimental results but also, which is even more desirable, for the prediction of new, hitherto unknown structures. 

A key requirement of QSAR is that the compounds used in the modeling and prediction processes should have the same mechanism of action, and for this reason most QSAR studies are made with congeneric series of compounds. However, if a diverse set of compounds can reasonably be assumed to have the same mechanism of action, QSAR modeling can justihably be carried out. For example, Dearden et al. [43] developed a QSAR for the ratio of brain levels of 22 very diverse drugs in the wild-type mouse and the P-glycoprotein knockout mouse (R+/ ) ... 

The same assumptions apply to CoMFA as to ordinary Hansch analysis. These are additivity of effects and the availability of structurally similar (congeneric) molecules. The method does not account for pharmacokinetic effects, such as distribution, elimination, transport and metabolization. A prospective drug may appear to bind well to the receptor or enzyme, but may not reach the target site due to undesirable pharmacokinetic properties [8]. 

However, from our point of view, there remains a lack of sufficiently precise and reliable methods to compute thermodynamic water solubility. The majority of methods work only for congeneric series of compounds, and many have not been developed to function in areas of pharmaceutical research using drug-like molecules. Most of the methods do not use the three-dimensional structure of the compounds, while some depend on previous knowledge of certain experimental properties of the compounds of interest. Moreover, all of the methods are dependent upon the quality of solubility values in the training set used to develop the model indeed, this latter point is a critical limitation that has a major influence on solubility estimations. 

Sophisticated drug-likeness models are normally used across a congeneric series of compounds to solve a specific problem in lead optimization. On the other hand, empirical rules are frequently used in lead finding. 

Herman, R. A. and P. Veng-Pedersen. 1994. Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not con ned to a congeneric sefi harm. Sci83 423-428. 

What has the very limited experience of the past few years using substituent constants and regression analysis contributed to the problem of drug modification as outlined for derivatives of Figure 1 Possibly the most important fact is that the hydrophobic character of the members of almost any congeneric set of drugs must be considered even in... 

Multiple Binding Modes. Realistically, congeneric series that can be a useful construct exist only in the mind of the medicinal chemist. The orientation of the drug in the active site depends on a multitude of interactions and a minor perturbation in structure can destabilize the predominant binding mode, in favor of another. As examples, detailed... 

Du-Cuny, L., Huwyler, J., Wiese, M. and Kansy, M. (2008) Computational aqueous solubility prediction for drug-like compounds in congeneric series. European Journal of Medicinal Chemistry, 43 (3), 501-512. 

Chemistry involved is not only graceful and stylish but also comparatively simple, whereby a few same reactions could suffice in yielding thousands of drug molecules in a specific congeneric series. 

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