title: Pharmacophore development and screening for discovery of potential inhibitors of ADAMTS-4 for osteoarthritis therapy.
abstract: In the development of osteoarthritis, aggrecan degrades prior to cartilage destruction. Aggrecanase-1 (ADAMTS-4) is considered to be the major enzyme responsible for cleaving the Glu373-Ala374 bond in the interglobular domain of aggrecan in humans. Therefore, inhibitors of ADAMTS-4 have therapeutic potential in the treatment of osteoarthritis. In the present work, we developed a chemical feature based pharmacophore model of ADAMTS-4 inhibitors using the HipHop module within the Catalyst program package in order to elucidate the structure-activity relationship and to carry out in-silico screening. The Maybridge database was screened using Hypo1 as a 3D query, and the best-fit hits that followed Lipinski's rule of five were subsequently screened to select the compounds. The hit compounds were then docked into the active site of ADAMTS-4, and interactions were visualized to determine the potential lead molecules. After subjecting all of the hits to various screening and filtering processes, 13 compounds were finally evaluated for their in vitro inhibitory activities. This study resulted in the identification of two lead compounds with potent inhibitory effects on ADAMTS-4 activity, with IC50 values of 0.042 μM and 0.028 μM, respectively. These results provide insight into the pharmacophoric requirements for the development of more potent ADAMTS-4 inhibitors. Graphical Abstract The aggrecan-degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. In this work, we used HipHop-based pharmacophore modeling and virtual screening of the Maybridge database to identify novel ADAMTS-4 inhibitors. These novel lead compounds act as potent and specific inhibitors for the ADAMTS-4 enzyme and could have therapeutic potential in the treatment of OA.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Verma
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
authors.forename: Krishna
authors.initials: K
authors.lastname: Dalal
authors.affiliation: Laboratory of Molecular Modeling & Drug Design, Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India. mchopradu@gmail.com.
authors.forename: Madhu
authors.initials: M
authors.lastname: Chopra
mesh_terms: D000071121:ADAMTS4 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry; D055808:Drug Discovery; D006801:Humans; D062105:Molecular Docking Simulation; D010003:Osteoarthritis / Q000188:drug therapy / Q000201:enzymology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000627:therapeutic use
chemical_list: D011480:Protease Inhibitors; D000071121:ADAMTS4 Protein
keywords: Aggrecanase; Docking; HipHop; Inhibitor; Osteoarthritis; Pharmacophore modeling; Virtual screenin