Improved Alignment by Weighted Field Fit in CoMFA of Histamine H2 Receptor Agonistic Imidazolylpropylguanidines

Abstract

More realistic description of ligand-receptor interactions in CoMFA results from alignments considering surface and ®eld properties instead of only molecular frameworks. The ®eld ®t algorithm implemented in SYBYL (Tripos Ass.) as part of the energy minimizer provides the possibility to assign individual weights to grid points. A new weighting function derives the signi®cance of grid points for the alignment of ®elds from preceding CoMFA runs, using regression coef®cients, means, and standard deviations of ®eld variables as parameters. Just in strongly diverse congeneric series, the method does not underestimate the common structure and not overweight variable, interacting regions. CoMFA of a large series of 142 histamine H 2 receptor agonistic imidazolylpropylguanidines (pD 2 values from guinea pig atrium) is presented as example. Results with three different alignments were compared: (1) exact superposition of the constant imidazolylpropylguanidine moiety, (2) SUPERIMPOSE or FIT of energy minima, (3)

Computational investigation of interactions between human H2 receptor and its agonists

“…3). The best pharmacophore was selected based on previous studies [15,16,22,23] and the following QSAR indicators. As illustrated in Fig.…”

“…From the superposition of the agonists with the pharmacophore, there were no pharmacophore features mapping to the chiral centre in alkyl side chains, so the chirality of the compounds were ignored. The chirality was also neglected in pervious 3D-QSAR study on the H 2 agonists [15,16], and experiments also demonstrated that ␣ or ␤ position chirality played minor role in H 2 activation [48]. When PLS factor was set as 3, the best QSAR model was obtained with R 2 = 0.90 for the training set and Q 2 = 0.66 for the test set (Fig.…”

“…Computer-aided methods, such as 3D-QSAR analysis, have been used to study the guanidine-type agonists and valuable information was obtained [15,16]. It was confirmed that branching at the third C atom after the guanidino group could increase the activity of the agonists [9,10].…”

Structural Requirements for Inhibition of the Neuronal Nitric Oxide Synthase (NOS-I): 3D-QSAR Analysis of 4-Oxo- and 4-Amino-Pteridine-Based Inhibitors

“…Similar weights were assigned to all grid points, although improved results with individual weighting were reported. 60 Subsequently, applying the rigid realignment procedure produced alignments C2 and C3. Finally, an unconstrained energy minimization was used to relax every molecule from internal strain, producing alignment C4.…”

Automatic generation of alignments for 3D QSAR analyses

“…The use of the routine has been reported by several workers (see, e.g., [33][34][35]) but is quite complex in operation [36], involving the inclusion of weighted field-fit energy penalties as additional parameters in the Tripos force field. More recently, Paretti et al have described a procedure that is analogous to that reported here [20] but that uses Monte Carlo and simplex procedures for the generation of the alignments, rather than a GA, and PLS analysis of N×N similarity matrices, rather than CoMFA and CoMSIA.…”