3D-QSAR CoMFA of a Series of DABO Derivatives as HIV-1 Reverse Transcriptase Non-Nucleoside Inhibitors

Abstract

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by comparative molecular field analysis (CoMFA) in order to derive three-dimensional quantitative structure-activity relationship (3D-QSAR) models. The CoMFA study has been performed with a training set of 59 compounds, testing three alignments and four charge schemes (DFT, HF, AM1, and PM3) and using defaults probe atom (Csp (3), +1 charge), cutoffs (30 kcal.mol (-1) for both steric and electrostatic fields), and grid distance (2.0 A). The best model ( N = 59), derived from Alignment 1 and PM3 charges, shows q (2) = 0.691, SE cv = 0.475, optimum number of components = 6, r (2) = 0.930, SEE = 0.226, and F-value = 115.544. The steric and electrostatic contributions for the best model were 43.2% and 56.8%, respectively. The external predictive ability (r (2) pred = 0.918) of the resultant best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, attention should be taken in order to select a substituent for the 4-oxopyrimidine ring, since, as revealed by the best CoMFA model, there are a steric restriction at the C2-position, a electron-rich group restriction at the C6-position ( para-substituent of the 6-benzyl group), and a steric allowed region at the C5-position.

Computational modeling studies on anti-HIV-1 non-nucleoside reverse transcriptase inhibition by dihydroalkoxybenzyloxopyrimidines analogues: an electrotopological atomistic approach

“…A series of 74 compounds of DABO derivatives was taken from the literature [28] for the QSAR study. All the 74 compounds were sketched using V-life MDS software [41].…”

“…Dihydroalkoxybenzyloxopyrimidines (DABO) derivatives have been successfully used as HIV-1 reverse transcriptase inhibitors [24] and are useful precursors for deriving novel potent compounds. The first step of rational drug design often consists of performing QSAR modeling, based on congeneric structures of ligands; this procedure has been carried out by several researchers for a class of DABO derivatives [25][26][27][28]. Like other NNRTIs, DABOs also assume a "butterfly like" spatial arrangement with the methylene group or moiety serving as a bridge between the two wings of the benzene and pyrimidine rings [27].…”

“…Like other NNRTIs, DABOs also assume a "butterfly like" spatial arrangement with the methylene group or moiety serving as a bridge between the two wings of the benzene and pyrimidine rings [27]. 5-isopropyl-2-[(methylthiomethyl)thio]-6-benzylpyrimid in-4-(1H)-one DABO analogue was found to be very potent against HIV-1 Reverse Transcriptase (RT) [28]. Dihydro-alkyl-thio-benzyl-oxopyrimidines (S-DABOs) are common with EBUs (Emivirine, formerly MKC-442) in having a benzyl moiety at position C-6 of the pyrimidine ring while they differ from EBUs in that the alkoxy chain is linked at position C-2 instead of N-1.…”

“…Thus, for the first time a QSAR study based on KierHall Electrotopological State (E-State) [39][40][41] indices is performed on DABO derivatives to analyze the pharmacophoric effect on their inhibitory activities. Recently, a comparative molecular field analysis (CoMFA) study was performed in order to derive three-dimensional quantitative structure activity relationship (3D-QSAR) models of DABO analogues [28]. The rationale of the present work is to explore the structure activity relationship of E-State indices of DABO compounds and the biological activity in a quantitative manner using linear (MLR) as well as non-linear (NN and k-NN) techniques.…”

3D-QSAR and docking studies on piperidine-substituted diarylpyrimidine analogues as HIV-1 reverse transcriptase inhibitors

“…A proper alignment can make molecules to be represented with comparable conformations and consistent orientations. Currently, there are three basic kinds of alignment methods: substructure based, pharmacophore based and docking based, and these (Brito et al, 2008;Liu et al, 2014;Vyas et al, 2014;Weber et al, 2010). In this study, substructure-based and docking-based methods were used to align the molecules, and the corresponding results were carefully compared in order to find the better method for model constructions.…”