caa a22 4500 469053461 CHVBK 20180323132836.0 cr unu---uuuuu 170328e19920601xx s 000 0 eng 10.1007/BF00123380 doi (NATIONALLICENCE)springer-10.1007/BF00123380 PLS modelling of structure—activity relationships of catechol O -methyltransferase inhibitors [Elektronische Daten] [Timo Lotta, Jyrki Taskinen, Reijo Bäckström, Erkki Nissinen] Summary: Quantitative 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. ESCOM Science Publishers B.V, 1992 QSAR nationallicence Computational chemistry nationallicence PLS nationallicence Multivariate nationallicence COMT nationallicence Catechols nationallicence Lotta Timo Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut Taskinen Jyrki Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut Bäckström Reijo Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut Nissinen Erkki Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 6/3(1992-06-01), 253-272 0920-654X 6:3<253 1992 6 10822 https://doi.org/10.1007/BF00123380 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00123380 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lotta Timo Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut NATIONALLICENCE 700 1- Taskinen Jyrki Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut NATIONALLICENCE 700 1- Bäckström Reijo Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut NATIONALLICENCE 700 1- Nissinen Erkki Orion Research Center, Orion Corporation, Orion-Farmos Pharmaceuticals, P.O. Box 65, SF-02101, Espoo, Finland aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 6/3(1992-06-01), 253-272 0920-654X 6:3<253 1992 6 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer