Dove, Stefan and Buschauer, Armin (1997) Stepwise leave-one-isomer-out free-Wilson approaches as preprocessing tools in QSAR analysis of racemates. QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS, 16 (1). pp. 11-19. ISSN 0931-8771
Full text not available from this repository.Abstract
QSAR analysis of racemates is complicated if specific substituent-receptor interactions and, by that, specific spatial fits to the binding site result in individual but unknown activity differences of enantiomers, and even in structure-dependent changes of which is the more active configuration. In a first approximation, additivity of substituent contributions should be assumed instead of major conformational effects. Then, Free-Wilson analysis (FWA) can be used as preprocessing tool to reduce a starting set of all pairs of enantiomers into a final series of the probably (more) active configurations. A stepwise ''leave-one-isomer-out'' approach is applied, where the model is successively improved by checking all remaining pairs and leaving out one enantiomer, determined by a special criterion of poorest prediction, in each step. The final model is given by the maximal F value. This approach was applied to histamine HI antagonistic activity (pK(B), guinea pig ileum) of 19 racemic and six non-chiral phenyl-halogenated N-(diphenylpropyl)-N'-(imidazolylpropyl)guanidines. Based on only eight variables because of additivity of meta and para contributions, the starting model with n = 44, r(2) = 0.29, s = 0.52, F = 1.8, r(2)-PRESS = -0.14 has been improved to a final one with n = 31 (only six remaining pairs), r(2) = 0.84, s = 0.24, F = 14.0, r(2)-PRESS = 0.65 Additionally, each of the successive series was submitted to CoMFA. Statistical parameters of the parallel CoMFA and FWA models are closely related. QSAR results obtained with both methods correspond to well-known structure-activity relationships of diphenhydramine-like H-1 antagonists. A direct application of the leave-one-isomer-out strategy to CoMPA was less successful.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTAMINE; free-Wilson analysis; CoMFA; QSAR of racemates; leave-one-out approaches; histamine H-1 receptor antagonists |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 May 2023 11:25 |
| Last Modified: | 16 May 2023 11:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/51089 |
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