Molecular dynamics simulated validation of anti-cancerous alkaloids as Topo IIβ inhibitors screened by QSAR, pharmacophore and molecular docking approaches

Abstract

Looking to the recent roles of topoisomerases in various types of cancers, in the present paper, a quantitative structure–activity relationship model, based on genetic function approximation (GFA) method, was developed using 41 olivacine derivatives as inhibitors of topoisomerase IIβ (Topo IIβ). The best predictive GFA model explained the biological activity of the training and test sets with correlation coefficient values (r 2) of 0.747 and 0.549, respectively, and a significant cross-validated correlation coefficient (q 2) of 0.525. The model suggested positive correlation between activity and descriptors, namely partition coefficient (ALogP), electrostatic energy, number of hydrogen bond acceptors and number of rotatable bonds, while those of negative correlations with Jurs RPCG, Jurs TASA and PHI. Furthermore, a common feature-based pharmacophore model for these inhibitors was also developed which comprised of five features, namely one H-bond acceptor, two ring aromatic, one positive ionizable and one hydrophobic group. Screening of a large database for natural compounds, using both these developed models, led to identification of the pyrrole derivative, namely 1-(2-(dimethylamino)ethyl)-3-hydroxy-4-(4-methoxy-2-methylbenzoyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrrol-2(5H)-one (compound ID: STOCK1N-31995) with a predicted IC50 value of 0.3 × 10−6 µM as most potent inhibitor of Topo IIβ. The result of virtual screening was further validated using molecular dynamics (MD) simulation analysis. Thus, a 15 ns MD simulation analysis revealed high stability and effective binding of 1-(2-(dimethylamino)ethyl)-3-hydroxy-4-(4-methoxy-2-methylbenzoyl)-5-(3,4,5-trimethoxyphenyl)-1H-pyrrol-2(5H)-one within the active site of Topo IIβ.