ADAMTS4 (Aggrecanase-1) is an important enzyme, which belongs to ADAMTS family.
Aggrecanase-1 is involved in aggrecan degradation of articular cartilage in osteoarthritis and
rheumatoid arthritis. Overall variability of S1’ domain of ADAMTS4 has been the main selectivity
determinant to design the unique inhibitors. 34 inhibitors from Binding database and literature were
used to develop the pharmacophore model. The five featured pharmacophore model AHHRR had the
best survival score of 3.493 and post-hoc score of 2.545, indicating that the model is highly reliable.
The 3D-QSAR acquired had excellent r2 value of 0.99 and GH score of 0.839. The validated
pharmacophore model was used for insilico screening of Asinex and ZINC database for finding the potential lead
compounds. ZINC00987406 and ASN04459656 which pose high glide score i.e >7 Kcal/mol and H-bond and
hydrophobic interactions in the S1‘loop residues of ADAMTS4 were subjected to Molecular Dynamics Simulation
studies. Molecular dynamic simulation result indicates that the RMSD and RMSF of backbone atoms for the above
complexes were within the limit of 2.0 A˚. These compounds can be potential candidates for osteoarthritis by inhibiting
Keywords: ADAMTS4, pharmacophore, enrichment studies, docking studies, 3D-QSAR, molecular dynamics.
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