Nanochemistry and biotechnology

Quantum chemical modeling of the interaction of new acridine-based telomerase inhibitors with a parallel DNA quadruplex 
Ilchenko M.M., Dubey I.Ya.
Institute of Molecular Biology and Genetics, NAS of Ukraine, 150 Zabolotnogo str., 03680 Kyiv, Ukraine 
E-mail: dubey@imbg.org.ua 

G-quadruplexes (G4) are non-canonical nanosize structures formed by some guanine-rich DNA sequences, e.g. those at the ends of the telomeres, and based on the stacks of guanine quartets coordinated by K+ or Na+ cations. Their stabilization with small molecules results in the inhibition of telomerase and antitumor effect. 
We have recently proposed new telomerase inhibitors with high affinity to G4 DNA based on acridine core containing two basic fragments, namely pyridyl and N,N-dialkylaminoalkyl groups, able to interact with G4 phosphates [1]. Here we present the results of quantum chemical study of their binding to a parallel-type quadruplex formed by Tel22 oligonucleotide d[AGGG(TTAGGG)3], a fragment of human telomeric DNA (Protein Data Bank code 1KF1). 
All calculations of G4-ligand complexes were carried out in water by semi-empirical PM7 method (MOPAC-2012 software) using COSMO solvent model. Structures and energetic parameters of Tel22 quadruplex complexes with a series of acridine derivatives were obtained (Fig. 1). The main factors determining the complex stability were found to be the π-stacking of ligand heteroaromatic core with a terminal guanine quartet and ionic interaction of the protonated basic substituent with phosphate anion. Pyridyl residue is also able to form hydrophobic bonds with DNA bases further enhancing the ligand affinity. The obtained data will be used for the design of more efficient G4 ligands as potential antitumor drugs. 

Fig. 1. The calculated structure of Tel22 G4 complex with acridine derivative. K+ ions and interacting DNA phosphate and protonated nitrogen atom of Me2N group are shown as spheres. 

1.	Negrutska V.V., Saraieva I.V., Kostina V.G., Alexeeva I.V., Lysenko N.A., Dubey I.Ya. Telomerase inhibition by new di- and trisubstituted acridine derivatives // Biopolym Cell.-2016.-32.-P. 468-471.