Enzyme Hansch analyses

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]. 

QSAR Correlation. Statistical quality of QSAR correlation can be employed as a third criterion of commonality of mechanism. This approach can prove very meaningful when coupled with a mechanistic interpretation of the role of molecular descriptors used in the correlation, and with the significance of the slope and intercept. The quality of statistical fit and the interpretation of the parameter or parameters used in the correlation can provide a valuable insight into molecular mechanism. Recently, Hansch analysis has been combined with molecular graphics and modeling studies in which the activities of a series of substrates to an enzyme receptor have been related to the hydrophobic, electronic, and steric requirements for reversible binding... 

Equations (17) and (18) cannot be used directly for predictive purposes since they only describe and identify the components and not the original p/50 values directly. They clearly show, however, what the physical nature of the components is and in what direction stracture / has to be varied in order to arrive at more potent derivatives. True equations in the sense of a QSAR could have been obtained by the already mentioned special target rotation of Weiner and Malinowski, which would lead to a direct replacement of the abstract P j by molecule parameters according to equation (15). This, however, would not add new information in the present case, at least not for the three enzyme systems. For the ascites test the situation is a little different since here a small contribution of the first component in addition to the second component is present. If a Hansch analysis is directly applied to the experimental data of ascites inhibition alone a relation with % very similar to equation (18) is again obtained which can, however, be improved slightly by adding an electronic term. 

The inhibition was noncompetitive. Modification of 1-phenoxy-methyl-5 -dihydroisoq,uinoline did not lead to a great increase in activity. A Hansch analysis led to the conclusion that optimum activity had been achieved and also indicated that there was a correlation between enzyme inhibition, the hydrophobic constant, and the dipole moment. ... 

Hansch and Verma contribute to the quantitative structure-activity relationship (QSAR) analysis of heterocyclic topoisomerase I and II inhibitors. These inhibitors, known to inhibit either enzyme, act as antitumor agents and are currently used in chemotherapy and in clinical trials. 

The classical QSAR methodology started 1964 with the publications of Hansch and Fujita (1964) and Free and Wilson (1964) and the statement of Hansch (1969) resulted from a proposal by Fujita. They proposed to combine several physiochemical parameters (tt, a), also called descriptors, in a quantitative model. This Hansch-type analysis is very flexible and describes many different kinds of biological activities, e.g. in vitro data such as enzyme inhibition (Kubinyi 2002) ... 

C. Hansch and E. Coats, a-Chymotrypsin A Case Study of Substituent Constants and Regression Analysis in Enzymic Structure-Activity Relationships, J. Pharm. Sci., 1970, 59, 731. 

Hansch C, Coats E. Chymotrypsin a case study of substituent constants and regression analysis in enzymic structure-activity relationships. J Pharm Sci 1970 59 731-743. 

Analysis of the fly-head acetylcholinesterase data by multiple regression showed that the equilibrium constant for the enzyme-inhibitor complex is related to Hansch s n-constant and ring position terms. Reversible binding of these compounds to acetylcholinesterase probably occurs through hydrophobic bonding (Wustner et al., 1978). 

Baker has developed an approach to selective cytotoxicity based on active-site-directed irreversible inhibitors that combine reversibly with the target enzyme and then inactivate it by exo-alkylation. Using this approach, he has prepared compounds that in vitro selectively inactivate folate reductase from leukemia L1210, but not the enzyme from mouse liver, spleen, and intestine. to vivo, however, the only compound that was effective in prolonging the life of mice with L1210 leukemia did not show selectivity for the reductase from leukemic cells. Hansch has applied regression analysis to a series of pyrimidine and triazine inhibitors of folate reductase. ... 

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