Journal of Molecular Graphics and Modelling 29 (2010) 229–239 Contents lists available at ScienceDirect Journal of Molecular Graphics and Modelling journal homepage: www.elsevier.com/locate/JMGM Development of highly predictive 3D-QSAR CoMSIA models for anthraquinone and acridone derivatives as telomerase inhibitors targeting G-quadruplex DNA telomere Vishal P. Zambre, Prashant R. Murumkar, Rajani Giridhar, Mange Ram Yadav ∗ Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, The M.S. University of Baroda, Vadodara 390001, Gujarat, India article info Article history: Received 17 February 2010 Received in revised form 7 July 2010 Accepted 9 July 2010 Available online 15 July 2010 Keywords: CoMSIA Anthraquinone Acridone Telomerase inhibitors Intercalators abstract G-quadruplex structures of DNA represent a potentially useful target for anticancer drugs. Telomerase enzyme, involved in immortalization of cancer cells is inhibited by stabilization of G-quadruplex at the ends of chromosomes. Anthraquinone and acridone derivatives are promising G-quadruplex ligands as telomerase inhibitors. So far, optimization of these ligands remained hampered due to the lack of cred- itable quantitative structure–activity relationships. To understand the structural basis of anthraquinone and acridone derivatives, a predictive 3D-QSAR model has been developed for the first time for telomerase inhibitory activity of G4 ligands, employing comparative molecular similarity indices analysis (CoMSIA). Considering the proposition that the basic nitrogens in these compounds should exist in protonated form at physiological pH the protonated forms of the reported compounds were analyzed and investigated. The QSAR model from conformational template Conf1 exhibited best correlative and predictive proper- ties. The actual predictive abilities of the QSAR model were thoroughly validated through an external validation test set of compounds. The statistics indicate a significantly high prediction power of the best model (r 2 , 0.721), supporting the proposed molecular mechanism of DNA G-quadruplex ligands. © 2010 Elsevier Inc. All rights reserved. 1. Introduction Telomerase is a complex ribonucleoprotein reveres transcrip- tase enzyme. RNA template (hTR) and a catalytic protein domain (hTERT) are two major components of human telomerase [1]. Telomeric DNA consists of repetitive guanine-rich sequences which forms secondary structures based on reverse Hoogsteen-type base pairing involving four guanines in a planar arrangement termed G- tetrad [2,3]. Telomere length progressively shortens in somatic cells with successive rounds of cell division, leading eventually to senes- cence and apoptosis. In contrast telomere length is maintained in cancer cells and is a major factor in immortalization and tumorigen- esis [4]. This happens almost always under activation of the enzyme telomerase [5] which has made it a highly selective target for anti- tumor drug design [6,7]. Various strategies have been proposed to induce telomerase inhibition [8]. A promising strategy is based on the inhibition of telomerase by interacting with G-quadruplex DNA. G-quadruplex DNA interactive compounds inhibit telomerase in vitro by stabilizing single stranded 3 ′ -telomere ends as a quadru- plex [9,10]. The best example is a ligand called quarfloxacin ∗ Corresponding author. Tel.: +91 265 2434187; fax: +91 265 2418927. E-mail addresses: mryadav11@yahoo.co.in, mryadav-phar@msu.ac.in (M.R. Yadav). (formerly CX-3543) that is now in phase-II clinical trial as an anti- cancer agent [11]. Substituted acridines and anthraquinones have been reported previously [12,13] to stabilize G-quadruplex. Campbell et al. reported structural basis of DNA quadruplex recognition by an acridine drug (BRACO-19) [14] and also discussed issues related to selectivity in ligand recognition of G-quadruplex loop [15]. Acridone derivatives are another class of ligands that stabilize the G-quadruplex structures possessing comparable telomerase inhibitory activity to acridine derivatives [16]. Harrison et al. [16], Read et al. [17], and Perry et al. [18,19] carried out structure–activity relationship studies of telomerase inhibitors. Effects of amide bond direction on modulation of G- quadruplex recognition and telomerase inhibition by substituted anthracenedione derivatives have studied [20]. Recently, Cuenca et al. postulated that the incorporation of aromatic side chains to the acridone core in the 4 and 5 position would enhance G-quadruplex affinity, although these derivatives did not show telomerase inhibitory activity [21]. A three-dimensional structure–activity relationship (3D-QSAR) as rational basis for the G-quadruplex ligand optimization for anthraquinones and acridones remains unreported. With 3D-QSAR analysis it is possible to analyze the probable structural elements affecting the biological activity of compounds. We have been involved in the computer aided designing of novel acridine derivatives as telomerase inhibitors 1093-3263/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2010.07.003