Ligand-based Pharmacophore Modeling Studies of TNF- alpha- converting enzyme Inhibitors

Thangavel Muthusamy; Devaprasad Markandeyan; Mariappan Andi; Abhinand.P.A; Subramaniyan Kannaian

Volume : IX, Issue : II, February - 2019

Ligand-based Pharmacophore Modeling Studies of TNF- alpha- converting enzyme Inhibitors

Thangavel Muthusamy, Devaprasad Markandeyan, Mariappan Andi, Abhinand. P. A, Subramaniyan Kannaian

Abstract :

Aim: Tumor necrosis factor–α converting enzyme (TACE ) is a metalloproteinase which cleaves Pro–TNF–α protein at its Ala76–Val77 amide bond, thereby releasing a soluble 17kDa ectodomain which mediates various proinflammatory activity of cytokine Tumor necrosis factor–α (TNF–α ). TACE is promising target for treatment of various autoimmune diseases like Multiple Sclerosis, Psoriasis, Rheumatoid arthritis etc. We have built ligand–based pharmacophore and 3D–QSAR models based on TACE inhibitors with known IC50 values using PHASE software of Schroedinger. Methods: We found that model AADDR.144 has highest R2 value (0.9921), Pearson R value of 0.6698 and a low Standard Deviation (SD) of 0.0761 and Root–Mean– Square–Error value (RMSE) of 0.6433.Validation using training and test set compounds was done. Results: The generated 3D–QSAR model was found to be useful in predicting activities of new ligands. Screening of Phytochemicals was done and phytochemicals which are similar to the AADDR.144 model were further docked to TACE protein GLIDE software. Conclusion: Phytochemical compounds Delphinidin, Canthin 6–one glucoside, Malvidin, Myrecetin, Amentoflavone, Hesperidin have good structural similarity to QSAR model built based on known TACE inhibitors and these compounds also have good binding affinity to TACE protein in docking