3D-QSAR study of hallucinogenic phenylalkylamines by using CoMFA approach

Abstract

The three-dimensional quantitative structure-activity relationship (3D-QSAR) has been studied on 90 hallucinogenic phenylalkylamines by the comparative molecular field analysis (CoMFA). Two conformations were compared during the modeling. Conformation I referred to the amino group close to ring position 6 and conformation II related to the amino group trans to the phenyl ring. Satisfactory results were obtained by using both conformations. There were still differences between the two models. The model based on conformation I got better statistical results than the one about conformation II. And this may suggest that conformation I be preponderant when the hallucinogenic phenylalkylamines interact with the receptor. To further confirm the predictive capability of the CoMFA model, 18 compounds with conformation I were randomly selected as a test set and the remaining ones as training set. The best CoMFA model based on the training set had a cross-validation coefficient q (2) of 0.549 at five components and non cross-validation coefficient R (2) of 0.835, the standard error of estimation was 0.219. The model showed good predictive ability in the external test with a coefficient R (pre) (2) of 0.611. The CoMFA coefficient contour maps suggested that both steric and electrostatic interactions play an important role. The contributions from the steric and electrostatic fields were 0.450 and 0.550, respectively.

3D-QSAR Analysis on Pyrrolopyridine Analogs as Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK-2) Inhibitors

“…Blue-colored regions show areas where electropositive charged groups enhance MK-2 inhibitory activity, while red regions represent where electronegative charged groups improve the activity. (12), (15) and (18) (with a substituents at the 3-position) have more inhibitory activity than compounds (11), (14) and (17). At the 2-position, there is a relatively large blue region and a small yellow region.…”

“…If electron-rich substituents occupy the blue contour and bulky substituents occupy the yellow contour, this will depress the biological activity. Consequently, compounds (11), (14) and (17), with 2-hydroxy, 2-chloro and 2-fluoro substituents, respectively, are lower activity than compound (3). The large red polyhedra encircling the benzene ring at the 4-positions indicate electronegative charged groups for 4-substitution on phenyl ring were favorable, which appears to account for the good activity of some compounds with electron-rich substituents such as compounds (13), (16), (19), (24) and (25), etc.…”

“…Introduced in 1988, a comparative molecular field analysis (CoMFA) [11] has emerged as a powerful tool in drug *Address correspondence to this author at the College of Pharmacy, Jinan University, Guangzhou, 510632, China; Tel :(+86-20)-85224451; Fax: (+86-20)-85224766; E-mail: pharmacydoctor@163.com design [12][13][14]. In common with all QSAR methods, it is based on a numerical description of molecular structure and employs statistics to obtain a correlation.…”

DFT-based QSAR and Action Mechanism of Phenylalkylamine and Tryptamine Hallucinogens

“…Some knowledge on the activity of hallucinogens at molecular level and their QSARs had been reported, and several QSAR models also established with different approaches. [2][3][4][5][6][7] In this work, we carried out accurate calculations for the first time for selected hallucinogens on various electronic descriptors based on density functional theory (DFT) method using B3LYP hybrid functional 8 together with the 6-311＋G(d,p) basis set by Gaussian 03 package of programs. 9 We have established four new QSAR models for hallucinogenic activity by multiple linear regression (MLR) method.…”

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of thiazolone derivatives as hepatitis C virus NS5B polymerase allosteric inhibitors

“…Three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches, such as comparative molecular field analysis (CoMFA) [25] and comparative molecular similarity analysis (CoMSIA) [26] have been widely used in drug design [27,28]. In this investigation, several 3D-QSAR models were built for a series of thiazolone derivatives [24,[29][30][31] to gain insight into the key structural factors affecting their activity.…”