An alignment-free, three dimensional quantitative structure-activity relationship (3D-QSAR) analysis has been performed on a series of -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 ( ) 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, of 0.85, and leave-multiple-out. This model gives a remarkably high (0.66) for a test set of 10 compounds. Docking studies were performed to investigate the mode of interaction between -carboline derivatives and the active site of the most probable anticancer receptor, polo-like kinase protein. 1. Introduction The -carboline alkaloids, which are originally isolated from the medicinal plant Peganum harmala [1–3], 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 [4–6]. According to previous investigations, -carbolines exert a broad spectrum of pharmacological effects such as anxiolytic, sedative [7–9], antimicrobial [10, 11], antiviral [12], antithrombotic [13, 14], and antiparasitic effects [15, 16]; also they are associated with alcohol dependence [17], and neurological diseases such as Parkinson’s disease [18, 19]. Moreover, a large series of -carbolines have been reported for their affinity with several receptors such as imidazoline [20, 21], benzodiazepine (BZ) [22–24], 5-hydroxytryptamine (5-HT) [25, 26], and dopamine (DA) [27]. Recently, -carboline alkaloids have drawn attention due to their antitumor activity [5, 28–33] and their functions through multiple mechanisms such as their ability to intercalate into DNA helix, inhibiting topoisomerases I and II [34, 35], monoamine oxidase [36–39], CDK (cyclin-dependent kinases) [40, 41], and MK-2 [42]. -Carbolines have the potential to be used as anticancer drug leads. One of the major antitumor mechanisms is apoptosis in cultured HepG2 cells induced by -carbolines with downregulate the expression of Bcl-2 gene and upregulate the expression of death receptor Fas,without altering the level of Bax and P53 [43]. Previous data suggest that
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