PLS modelling of structure—activity relationships of catechol O-methyltransferase inhibitors

SummaryQuantitative structure-activity analysis was carried out for in vitro inhibition of rat brain soluble catechol O-methyltransferase by a series (N=99) of 1,5-substituted-3,4-dihydroxybenzenes using computational chemistry and multivariate PLS modelling of data sets. The molecular structural descriptors (N=19) associated with the electronics of the catecholic ring and sizes of substituents were derived theoretically. For the whole set of molecules two separate PLS models have to be used. A PLS model with two significant (crossvalidated) model dimensions describing 82.2% of the variance in inhibition activity data was capable of predicting all molecules except those having the largest R1 substituent or having a large R5 substituent compared to the NO2 group. The other PLS model with three significant (crossvalidated) model dimensions described 83.3% of the variance in inhibition activity data. This model could not handle compounds having a small R5 substituent, compared to the NO2 group, or the largest R1 substituent. The predictive capability of these PLS models was good. The models reveal that inhibition activity is nonlinearly related to the size of the R5 substituent. The analysis of the PLS models also shows that the binding affinity is greatly dependent on the electronic nature of both R1 and R5 substituents. The electron-withdrawing nature of the substituents enhances inhibition activity. In addition, the size of the R1 substituent and its lipophilicity are important in the binding of inhibitors. The size of the R1 substituent has an upper limit. On the other hand, ionized R1 substituents decrease inhibition activity.

[1]  J. Axelrod,et al.  Enzymatic O-methylation of epinephrine and other catechols. , 1958, The Journal of biological chemistry.

[2]  Nisse Kalkkinen,et al.  Purification and partial characterization of rat liver soluble catechol‐ O‐methyltransferase , 1990, FEBS letters.

[3]  I. E. Frank.  A nonlinear PLS model , 1990 .

[4]  E Nissinen,et al.  The site of O-methylation by membrane-bound catechol-O-methyltransferase. , 1984, Biochemical pharmacology.

[5]  S. Wold,et al.  Peptide quantitative structure-activity relationships, a multivariate approach. , 1987, Journal of medicinal chemistry.

[6]  P. Männistö,et al.  Synthesis of some novel potent and selective catechol O-methyltransferase inhibitors. , 1989, Journal of medicinal chemistry.

[7]  C Bohuon,et al.  Presence of two distinct catechol -O- methyltransferase activities in red blood cells. , 1971, Biochimie.

[8]  Johann Gasteiger,et al.  The Anesthetic Activity and Toxicity of Halogenated Ethyl Methyl Ethers, a Multivariate QSAR Modelled by PLS , 1985 .

[9]  Gabriele Cruciani,et al.  Principal Properties for Aromatic Substituents. A Multivariate Approach for Design in QSAR , 1989 .

[10]  Ulf Norinder,et al.  Experimental design based 3-D QSAR analysis of steroid-protein interactions: Application to human CBG complexes , 1990, J. Comput. Aided Mol. Des..

[11]  Svante Wold,et al.  Multivariate Parametrization of 55 Coded and Non‐Coded Amino Acids , 1989 .

[12]  C. Marsden,et al.  Catechol-O-methyl transferase: pharmacological aspects and physiological role. , 1975, Pharmacological reviews.

[13]  B. Skagerberg,et al.  Comparison of Chemometric Models for QSAR , 1990 .

[14]  Martti Ovaska,et al.  QSAR and Binding Model for Inhibition of Rat Liver Catechol-O-Methyl-Transferase by 1,5-Substituted-3,4-Dihydroxybenzenes , 1989 .

[15]  S. Wold.  Cross-Validatory Estimation of the Number of Components in Factor and Principal Components Models , 1978 .

[16]  D. E. Patterson,et al.  Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR Studies , 1988 .

[17]  Z Dembic,et al.  Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[18]  N. Kalkkinen,et al.  Molecular cloning and characterization of rat liver catechol-O-methyltransferase. , 1990, Gene.

[19]  S. Kaakkola,et al.  New selective COMT inhibitors: useful adjuncts for Parkinson's disease? , 1989, Trends in pharmacological sciences.

[20]  A. Jalanko,et al.  Cloning and Characterization of Human Placental Catechol--Methyltransferase cDNA , 1991 .

[21]  Marina Cocchi,et al.  QSAR Analysis in 2,4-Diamino-6,7-dimethoxy Quinoline Derivatives – α1-Adrenoceptor Antagonists – Using the Partial Least Squares (PLS) Method and Theoretical Molecular Descriptors , 1990 .

[22]  Svante Wold,et al.  A Strategy for Ranking Environmentally Occurring Chemicals. Part IV: Development of Chemical Model Systems for Characterization of Halogenated Aliphatic Hydrocarbons , 1991 .

[23]  Johann Gasteiger,et al.  Multivariate structure‐activity relationships between data from a battery of biological tests and an ensemble of structure descriptors: The PLS method , 1984 .

[24]  H Breuer,et al.  Interactions between estrogens and catechol amines. 3. Studies on the methylation of catechol estrogens, catechol amines and other catechols by the ctechol-O-methyltransferases of human liver. , 1972, The Journal of clinical endocrinology and metabolism.

[25]  S. Kaakkola,et al.  Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease. , 1988, The Journal of pharmacology and experimental therapeutics.

[26]  S. Wold,et al.  Nonlinear PLS modeling , 1989 .

[27]  D. Massart.  Chemometrics: A Textbook , 1988 .

[28]  P. J. Worsfold,et al.  Chemometrics: A Textbook (Data Handling in Science and Technology, Vol. 2) , 1989 .

[29]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .