ISSN:
1573-4951
Keywords:
3D-QSAR methodology
;
acetylcholinesterase active site
;
acetic acid esters
;
adjusted biological activity
;
bioactive conformation
;
MTD
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract The active conformation is part of a conformational mixture with experimental activity Yexp, and is used in QSAR studies to extract more information regarding the ligand-receptor interaction. To reflect the relative amount (α) of the active conformation, we adjust Yexp : Yadj = Yexp - log α. We establish a quantitative structure-activity relationship (QSAR) between Yadj and 3D conformational characteristics for the acetylcholinesterase (AChE) hydrolysis rates of 25 acetic esters. The 3D-QSAR model was obtained using the adjusted multiconformational minimal steric/topologic difference (MTD-ADJ) method, optimizing the receptor map based on Yadj for each conformer. Yadj was updated during each step of the optimization process. α and Yadj are based on the Boltzmann distribution calculated using AM1 (MOPAC 6.0) relative energies of the COSMIC 90 derived conformers. The MTD-ADJ results are: (i) the 3D-QSAR models obtained by this procedure have significant statistical parameters and are similar to the unadjusted (MTD-MC, using Yexp) models; (ii) the selected bioactive conformations are extended, occupy cavity vertices and, for the same structures, have the same MTD value; and (iii) the optimized conformational map of the neutral ligands obtained from the MTD-ADJ model fits well in the active site of the crystallographic structure of AChE (from Torpedo californica). We propose a neutral ligands binding site model for AchE. Our results show that MTD-ADJ, which can be implemented in any 3D-QSAR method, is capable of providing additional information regarding the active conformations, and can be used to gain further insight into the ligand-receptor models for which no structural data are available.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1007913622673
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