%0 Journal Article
%T Linear and Nonlinear QSAR Study of N2 and O6 Substituted Guanine Derivatives as Cyclin-Dependent Kinase 2 Inhibitors
%A Nasser Goudarzi
%A M. Arab Chamjangali
%A Payam Kalhor
%J ISRN Analytical Chemistry
%D 2013
%R 10.1155/2013/151464
%X The inhibitory activities (pIC50) of N2 and O6 substituted guanine derivatives as cyclin-dependent kinase 2 (CDK2) inhibitors have been successfully modeled using calculated molecular descriptors. Two linear (MLR) and nonlinear (ANN) methods were utilized for construction of models to predict the pIC50 activities of those compounds. The QSAR models were validated by cross-validation (leave-one-out) as well as application of the models for prediction of pIC50 of external set compounds. Also, the models were validated by calculation of statistical parameters and Y-randomization test. Two methods provided accurate predictions, although more accurate results were obtained by ANN model. The mean-squared errors (MSEs) for validation and test sets of MLR are 0.065, 0.069 and of ANN are 0.017 and 0.063, respectively. 1. Introduction The cyclin-dependent kinases (CDKs) are a class of enzymes which play a fundamental role in cell cycle regulation [1, 2]. Particularly as their name suggests CDKs activation partially depends on the binding of another class of proteins named cyclins, for example, cyclins of the D family complex with CDK4 and CDK6 during G1 phase, cyclin E with CDK2 in late G1, cyclin A with CDK2 in S phase, and cyclin B with CDK1 (also known as cdc2) in late G2/M. Then, aberrant CDK control and consequent loss of cell cycle check point function have been directly linked to the molecular pathology of cancer [3]. It is well known that phosphorylation in a conserved threonine residue of the CDK subunit is required for its complete activation. This task is performed by the CDK activating kinase. These proteins properly regulate the cell cycle progress and DNA synthesis only as an active complex (T160pCDK/cyclin) [4]. Overall, the activity of the CDK/cyclin complex can be depleted by at least two different mechanisms that contain the phosphorylation of the CDK subunit at the inhibitory sites or the binding of the specialized natural inhibitors known as CDK inhibitors. In the first mechanism, the amino acid residue Y15 and to a lesser extend T14 (in CDK2) are phosphorylated by human Wee 1 Hu [5]. This inhibitory phosphorylation is independent of previous cyclin binding [6]. The second mechanism involves the binding of natural CDK inhibitors. Four major mammalian CDK inhibitors have been discovered: P21 (CIP1/WAF190) and P27 (KIP1) inactive CDK2 and CDK4 cyclin complexes by binding to them. The two other inhibitors are and that are specific for CDK4 and CDK6. They inhibit the formation of the active cyclin complexes by binding to the inactive CDK, and they
%U http://www.hindawi.com/journals/isrn.analytical.chemistry/2013/151464/