Pharmacophore modeling and 3D-QSAR (CoMSIA) studies for structural requirements of some triazine derivatives as G-quadru
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Med Chem Res DOI 10.1007/s00044-012-0447-6
ORIGINAL RESEARCH
Pharmacophore modeling and 3D-QSAR (CoMSIA) studies for structural requirements of some triazine derivatives as G-quadruplex binders for telomerase inhibition Vishal P. Zambre • Rajani Giridhar Mange Ram Yadav
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Received: 3 July 2012 / Accepted: 20 December 2012 Ó Springer Science+Business Media New York 2013
Abstract Human telomeres are repetitive guanine rich sequences found at the ends of chromosomes that form special secondary structures known as G-quadruplexes. In majority of cancer cells, the telomerase enzyme has been found to maintain the length of telomeres, conferring cell immortality and prevention of cell senescence. Small molecules that bind and stabilize the G-quadruplex have proved to be potential telomerase inhibitors. The quantitative structure–activity relationships of triazine derivatives as G-quadruplex mediating telomerase inhibitors remain unclear. The objective of the study is to uncover structural requirements for triazine derivatives as G-quadruplex binders, which would eventually assist and complement the rational drug-design attempts for successful development of telomerase inhibitors as anticancer drugs. The model has been established by using a training set of compounds with cross-validated q2 0.593, non-cross-validated r2 0.976, standard error of estimate 0.167, and F test 115.130 for the best CoMSIA model. The predictive ability of the models was validated with the correlation coefficient r2pred 0.738 for the best CoMSIA model. The highly predictive 3D-model resulting from this study discovers the roles played by molecular features, mainly steric, hydrogen bond donor and hydrophobic properties.
V. P. Zambre R. Giridhar M. R. Yadav (&) Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Vadodara 390 001, Gujarat, India e-mail: [email protected]
Keywords Telomerase inhibitors G-Quadruplex binders Triazine derivatives CoMSIA Pharmacophore
Introduction Human telomeric DNA located at the end of chromosomes consists of repetitive guanine rich sequences which form secondary structures involving four guanines in a planar arrangement termed as G-quadruplex DNA (Blackburn, 1991; Burge et al., 2006). The building blocks of G-quadruplex are the G-quartets. G-quadruplex structures are higher order secondary structures where four G-rich DNA strands are held together via the formation of a G-quartet (Huppert, 2008). G-quadruplex structures are stabilized by small molecules in order to control gene expression and reverse tumor cell immortalization (Nemoto et al., 2007; Rodriguez et al., 2008). Stabilization of telomeric G-quadruplex by quadruplex-binding ligands inhibit telomerase function (Sun et al., 1997). Many groups have reported small molecules targeting G-quadruplex as telomerase inhibitors. (Li et al., 2012; Lu et al., 2008; Zagotto et al., 2008; Leonetti et al., 2008). Maintenance of telomere is important for the limitless proliferative potential of cancer c
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