Colorectal cancer, being a senescent disease, yet remains third most traditional disease in developed countries. Tankyrase, being a target for colorectal cancer, is a key regulator of WNT/B-catenin pathway. This research provides brief idea on development of novel Tankyrase inhibitors using Ligand-Based Drug Design. Pharmacophore was generated from seven diverse structures using GALAHAD module of Sybyl X1.3. The best generated pharmacophore contained 5 features viz. 1-donor, 1-acceptor and 3-hydrophobic features and validated by GH method. Virtual screening of validated pharmacophore model was used as a query in NCI database and various derivatives bearing pyrimidine moiety were obtained with good Q-fit value more than 85%. Along with this, 3D-QSAR study was also carried out using 41 pyrimidine derivatives and was validated by PLS analysis. This analysis provided good results with q2 value of 0.651 and 0.650 and predictive r2 value of 0.989 and 0.983 for CoMFA and CoMSIA models, respectively. Contour maps of CoMFA (steric and electrostatic) and CoMSIA (steric, electrostatic, hydrogen bond donor and acceptor, hydrophobic) were generated and provided information about hydrophobic feature which contributed well in increasing potency of Tankyrase inhibitors. Pharmacophore also contained 3 hydrophobic features which further provided useful information in designing the novel Tankyrase inhibitors. Designed novel Tankyrase inhibitors bearing pyrimidine moiety were docked on protein co-crystal structure (with PDB ID: 3KR7) with the help of SurFlex-Dock module of Sybyl and promising results were obtained with good docking score compared with standard molecule. Designed molecules showed interactions with conserved amino acids indicating that they bind with same pocket like of standard. In the end, it is concluded that with the help of ligand based drug design, a new series of potent molecules were designed which can help in development of a lead molecule in future for treatment of colorectal cancer

Ligand based drug design of novel pyrimidine derivatives as Tankyrase inhibitors for the treatment of colorectal cancer<br />

249th National Meeting (2015)

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