Autori: Sulea, Traian; Kurunczi, Ludovic; Oprea, Tudor I.; Simon, Zeno.

Editorial: J. Comput.-Aided Mol. Des., 12(2), p.133-146, 1998.

Rezumat:

The active conformation is part of a conformational mixt. with exptl. activity Yexp, and is used in QSAR studies to ext. more information regarding the ligand-receptor interaction. To reflect the relative amt. (a) of the active conformation, we adjust Yexp: Yadj = Yexp – log a. We establish a quant. 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/topol. difference (MTD-ADJ) method, optimizing the receptor map based on Yadj for each conformer. Yadj was updated during each step of the optimization process. a And Yadj are based on the Boltzmann distribution calcd. 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 crystallog. 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 addnl. 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.

Cuvinte cheie: Acetylcholinesterase, Conformation (ligand), Molecular association, MTD-ADJ, QSAR (structure-activity relationship), Receptor-binding