Developing consensus 3D-QSAR and pharmacophore models for several beta-secretase, farnesyl transferase and histone deacetylase inhibitors

Abstract

Three consensus 3D-QSAR (c-3D-QSAR) models were built for 38, 34, and 78 inhibitors of β-secretase, histone deacetylase, and farnesyltransferase, respectively. To build an individual 3D-QSAR model, the structures of an inhibitor series are aligned through docking of a protein receptor into the active site using the program GOLD. CoMFA, CoMSIA, and Catalyst are then performed for the training set of each structurally aligned inhibitor series to obtain a 3D-QSAR model. Since the consensus in features identified is high for the same pharmacophore features selected for building a 3D-QSAR model by a 3D-QSAR method, a c-3D-QSAR model for each inhibitor series is constructed by combining the pharmacophore features selected for building the 3D-QSAR model using the SYBYL spread sheet and PLS module. Each c-3D-QSAR pharmacophore model built was examined visually and compared with that obtained by simultaneous mapping of the corresponding 3D-QSAR pharmacophores built onto a selected inhibitor structure. It was found that the c-3D-QSAR model built for an inhibitor series improves not only the overall prediction statistics for both training and test sets but also the prediction accuracy for some less active inhibitors of the series.

Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE)

“…Most of these endeavors include computational studies such as pharmacophore modeling [14,15], classical quantitative structure-activity relationships (QSARs) [14-17], docking and virtual screening [18-22] and molecular dynamics (MD) simulations [23-26]. Currently, several hundred BACE-1 inhibitors have been reported, but most of these inhibitors are peptidomimetics [16].…”

Exploring the Efficacy of Noncovalent SARS‐CoV‐2 Main Protease Inhibitors: A Computational Simulation Analysis Study

“…The training set, composed of 28 compounds, was used to establish a 3D-QSAR model and verify the model's internal stability. [20] The test set, comprising the remaining 8 compounds, was employed to evaluate the model's external predictive capacity. This data will aid in understanding the inhibitory effects and structure-activity relationship of these compounds.…”

Farnesyltransferase Inhibitor in Cancer Treatment

“…This heterodimer has two distinct subunits denoted as and , having molecular weights of 48 kDa and 46 kDa respectively (Machida et al, 2011;Zhang & Casey, 1996). The X-ray crystal structure of FTase reveals that it has binding sites for both the CAAX peptide and the FDP (Kauh et al, 2011;Park et al, 1997;Wei et al, 2011). It has been shown that geranylgeranyltransferase can prenylate some of the substrates of FTase and vice versa.…”