Design, docking study and ADME prediction of Chalcone derivatives as potent Tubulin inhibitors

A series of piperonal chacones bearing schiff base moiety were designed and docked in to colchicine binding site of tubulin using the podophyllotoxin-tubulin complex (PDB 1SA1) as template. Docking study reveals that few of the designed derivatives were found to have significant interaction with active site of the receptor. The derivatives with trimethoxyphenyl ring, amino phenyl & nitro phenyl ring were found to have maximum docking score. In silico ADME predictions of most promising derivatives were also performed and compared. _____________________________________________________________________________________________ INTRODUCTION Drugs that target cellular microtubules can be divided into two groups, microtubule stabilizers and microtubule destabilizers, on the basis of their effects on tubulin polymerization and cellular microtubules. Colchicine is a microtubule depolymerizer that binds to tubulin at a site distinct from that of the vinca alkaloids. Although colchicine has not proven to be useful in the treatment of cancer, multiple compounds that bind within the colchicine site are advancing in clinical trials for anticancer indications. Chalcones represent an essential group of natural as well as synthetic products and some of them possess wide range of pharmacological activity.The previous research finding revealed that chalcone molecules have been extensively structurally modified and tested for their role in tubulin inhibition as potential anticancer compounds. Methylenedioxy moiety of benzodioxol is found to be present in some of currently used antitumor agents such as etoposide and teniposide which are glycosides of natural tubulin inhibitor called podophyllotoxin. Literature study revealed that this particular ring plays a key role in interacting with receptor. So the aim of the study was to design some chalcone derivatives of piperonal containing benzodioxol ring. MATERIALS AND METHODS Molecular docking The designed compounds were subjected to in silico screening .A number of structures of piperonal chalcones and Schiff base derivatives of piperonal chacones were drawn on drawing window of chemsketch and further explored for gross biological activity, which is comprised of Lipinski rules of 5, drug likeness, drug score. In silico docking experiments were performed using Schrodinger suite 2012 update1 and modules like Ligprep, quick prop, and glide were used in the study. The protein structure podophyllotoxin-tubulin complex (PDB 1SA1) was obtained from the RCSB PDB and was used for docking. Major possible mechanism and site of metabolism of most potent derivatives were also performed by MetaPrin2D software. Anwar P and Bobby S.P J. Comput. Methods Mol. Des., 2014, 4 (1):1-5 ______________________________________________________________________________ 2 Available online at www.scholarsresearchlibrary.com Figure 1 showing docking window of schrodinger software Figure 2 showing structures of potent derivatives Anwar P and Bobby S.P ______________________________________________________________________________ Available online a Prediction of Metabolism using MetaPrint2D MetaPrint2D is a a new software tool implementing a data metabolism. The algorithm is based on a statistical analysis of the occurrences of atom centred circula in both substrates and metabolites. In silico docking study showed that eight designed derivatives were having excellent affinity towards active site of tubulin. Ligand interaction diagram of most promising derivatives Figure 3 showing interaction of most potent ligands with amino acids of receptor J. Comput. Methods Mol. Des t www.scholarsresearchlibrary.com -mining approach for predicting sites of xenobiotic RESULTS ., 2014, 4 (1):1-5