Abstract—ADAMTS-5 is an important aggrecanase that cleaves at key sites in the aggrecan core protein, in healthy and diseased cartilage. ADAMTS-5 deficient mice are protected from cartilage erosion in models of experimental arthritis. Therefore inhibition of ADAMTS-5 will be a potential cure for arthritis. In this study pharmacophore model was developed by downloading 50 ligands with IC50 value from BindingDB database. Pharmacophore Alignment and Scoring Engine (PHASE) software was used to develop ligand-based pharmacophore model for ADAMTS-5 using those 50 ligands. pIC50 ranged from 7.3149 to 5.018, of which pIC50 above 6.5 were considered as active and below 5.5 were considered as inactive. Three maximum hypotheses AAHRR, AARRR, AHRRR were generated. Pharmacophoric hypothesis AARRR.4144 had the best survival score of 3. 3D-QSAR was built for the best hypothesis with training set as 70% and atom based model was generated by keeping 1Å grid spacing and 6 as maximum number of PLS factors. Results show that AARRR.4144 has the best regression coefficient of 0.9832 and Pearson-R as 0.756. A docking study revealed the binding orientations of these inhibitors at active site amino acid residue His 373 of ADAMTS-5. The results of ligand-based pharmacophore hypothesis and atom based 3D-QSAR gave detailed structural insights as well as highlighted important binding features to design a novel therapeutically active compound against ADAMTS-5. These features where used to screen natural compounds from Dukes Database and Hinokiflavone was identified as the best inhibitor with a glide score of -8.47Kcal/mol against Adamts-5. Therefore further studies can be carried on this natural compound to prove as a promising drug for osteoarthritis.

Index Terms—3D-QSAR, ADAMTS-5, Aggrecan, Docking, pharmacophore.

Rathi Suganya is with SRM University, Kattankulatur, Tamil Nadu, India. (phone: 9840796846; e-mail: rathisuganya@ ktr.srmuniv.ac.in).
Sukesh Kalva is with SRM University, Kattankulatur, Tamil Nadu, India. (phone: 9941452601; e-mail: Sukesh.kalva@ ktr.srmuniv.ac.in).
Lilly M. Saleena is with SRM University, Kattankulatur, Tamil Nadu, India. (corresponding author, phone: 9840506562; e-mail: lmsaleena@ yahoo.com).

Cite: Rathi Suganya P., Sukesh Kalva, Lilly M. Saleena, "Hinokiflavone from Juniperus as Therapeutic Leadagainst Osteoarthritis by Inhibiting ADAMTS-5," International Journal of Bioscience, Biochemistry and Bioinformatics vol. 1, no. 1, pp. 16-20, 2011.