Novel anthracenone derivatives were designed through in silico studies including 3D QSAR, pharmacophore mapping, and molecular docking approaches. Tubulin protein was explored for the residues imperative for activity by analyzing the binding pattern of colchicine and selected compounds of anthracenone derivatives in the active domain. The docking methodology applied in the study was first validated by comparative evaluation of the predicted and experimental inhibitory activity. Furthermore, the essential features responsible for the activity were established by carrying out pharmacophore mapping studies. 3D QSAR studies were carried out for a series of 1,5- and 1,8-disubstituted10-benzylidene-10H-anthracen-9-ones and 10-(2-oxo-2-phenylethylidene)-10H-anthracen-9-one derivatives for their antiproliferation activity. Based on the pattern recognition studies obtained from QSAR results, ten novel compounds were designed and docked in the active domain of tubulin protein. One of the novel designed compounds “N1” exhibited binding energy ？9.69？kcal/mol and predicted Ki 78.32？nM which was found to be better than colchicine. 1. Introduction Cancer is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all deaths) in 2008. The search for new anticancer drugs plays central role in the research programs of pharmaceutical companies and also for many governmental organizations [1]. Despite these efforts, the World Health Organization (WHO) estimates that the rate of incidence of such diseases will increase by 50% by the year 2020 [2]. It further projects that deaths from cancer worldwide may continue to rise over 11 million in 2030 [3]. For this reason, new and effective drugs are needed urgently. In recent years, a large number of anticancer agents have been discovered to act at different levels [4] and have higher efficacy and lower toxicity than existing treatments. These databases can be exploited with the help of automated and multivariate data analysis methods [5, 6]. The later relates the molecular structures with their biological properties by establishing computational models able to assign activity values to new untested compounds [7, 8]. In the present study we have targeted microtubule polymerization for the inhibition of tumor cell growth. Microtubules are polymeric protein complexes constructed from a heterodimer of two highly homologous proteins known as - and -tubulin. The assembly of tubulin heterodimers into a macromolecular microtubule complex is a tightly regulated and dynamic process [9]. They are involved in a
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