3D-QSAR and Docking Studies of a Series ofβ-Carboline Derivatives as Antitumor Agents of PLK1

Jahan B Ghasemi,Valentin Davoudian

doi:10.1155/2014/323149

Abstract

An alignment-free, three dimensional quantitative structure-activity relationship (3D-QSAR) analysis has been performed on a series ofβ-carboline derivatives as potent antitumor agents toward HepG2 human tumor cell lines. A highly descriptive and predictive 3D-QSAR model was obtained through the calculation of alignment-independent descriptors (GRIND descriptors) using ALMOND software. For a training set of 30 compounds, PLS analyses result in a three-component model which displays a squared correlation coefficient (r2) of 0.957 and a standard deviation of the error of calculation (SDEC) of 0.116. Validation of this model was performed using leave-one-out,q2looof 0.85, and leave-multiple-out. This model gives a remarkably highr2pred(0.66) for a test set of 10 compounds. Docking studies were performed to investigate the mode of interaction betweenβ-carboline derivatives and the active site of the most probable anticancer receptor, polo-like kinase protein.

Highlights

The β-carboline alkaloids, which are originally isolated from the medicinal plant Peganum harmala [1,2,3], comprise a planar tricyclic system with different degrees of aromaticity and various substituents at positions 1, 2, 3, 7, and 9; the presence, location, and nature of these substituents play a crucial role in biological and pharmaceutical properties of these compounds [4,5,6]
Β-carboline alkaloids have drawn attention due to their antitumor activity [5, 28,29,30,31,32,33] and their functions through multiple mechanisms such as their ability to intercalate into DNA helix, inhibiting topoisomerases I and II [34, 35], monoamine oxidase [36,37,38,39], CDK [40, 41], and MK-2 [42]. β-Carbolines have the potential to be used as anticancer drug leads
PLK1 contains an N-terminal catalytic domain and a C-terminal regulatory polo box domain (PBD) which is composed of two polo boxes

Summary

Introduction

The β-carboline alkaloids, which are originally isolated from the medicinal plant Peganum harmala [1,2,3], comprise a planar tricyclic system with different degrees of aromaticity and various substituents at positions 1, 2, 3, 7, and 9; the presence, location, and nature of these substituents play a crucial role in biological and pharmaceutical properties of these compounds [4,5,6]. Β-carboline alkaloids have drawn attention due to their antitumor activity [5, 28,29,30,31,32,33] and their functions through multiple mechanisms such as their ability to intercalate into DNA helix, inhibiting topoisomerases I and II [34, 35], monoamine oxidase [36,37,38,39], CDK (cyclin-dependent kinases) [40, 41], and MK-2 [42]. Previous data suggest that β-carbolines can inhibit the activity of polo-like kinases (PLKs). Among the four members of PLKs which are a family of serine-threonine kinases, PLK1 plays the most crucial role in cell proliferation and is an important regulatory enzyme in the G2/M transition through phosphorylation of substrates [46]. Since the PBD is contributing to PLK1 localization and Journal of Chemistry function, the PBDs of PLK1 are promising alternative targets for designing novel antitumor drugs [47, 48]

Objectives

Methods

Results