title: Design of selective TACE inhibitors using molecular docking studies: Synthesis and preliminary evaluation of anti-inflammatory and TACE inhibitory activity.
abstract: Tumor necrosis factor-α (TNF-α) converting enzyme (TACE) has been considered one of the principal therapeutic targets for the treatment of TNF-dependent pathologies. Several TACE inhibitors have been reported, but none of them has been successfully passed to phase II clinical trials. In the present work, we attempted to design highly selective new non-hydroxamate sulfonamide TACE inhibitors. The docking study was performed on one of the crystal structures of TACE, selected based on its resolution and R value, to tackle the flexibility issue of the active site. The results allowed us to distinguish the analogues with a higher binding affinity toward the active site of TACE and to identify the substituent of analogues needed for binding with the surrounding site of the enzyme. Finally the analogues were docked on crystal structures of six different matrix metalloproteinases (MMPs) for a selectivity study of TACE over MMPs. Some of these analogues were synthesized and subjected to preliminary testing for in vivo anti-inflammatory activity and TACE inhibitory activity.
authors.affiliation: a Department of Pharmaceutical Chemistry , Sinhgad Institute of Pharmacy , Pune , Maharashtra , India.
authors.forename: A P
authors.initials: AP
authors.lastname: Sarkate
authors.affiliation: a Department of Pharmaceutical Chemistry , Sinhgad Institute of Pharmacy , Pune , Maharashtra , India.
authors.forename: P R
authors.initials: PR
authors.lastname: Murumkar
authors.affiliation: b Department of Chemical Technology , Dr. Babasaheb Ambedkar Marathwada University , Aurangabad , Maharashtra , India.
authors.forename: D K
authors.initials: DK
authors.lastname: Lokwani
authors.affiliation: c Department of Pharmacology , Poona College of Pharmacy, Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: A D
authors.initials: AD
authors.lastname: Kandhare
authors.affiliation: c Department of Pharmacology , Poona College of Pharmacy, Bharati Vidyapeeth Deemed University , Pune , Maharashtra , India.
authors.forename: S L
authors.initials: SL
authors.lastname: Bodhankar
authors.affiliation: b Department of Chemical Technology , Dr. Babasaheb Ambedkar Marathwada University , Aurangabad , Maharashtra , India.
authors.forename: D B
authors.initials: DB
authors.lastname: Shinde
authors.affiliation: a Department of Pharmaceutical Chemistry , Sinhgad Institute of Pharmacy , Pune , Maharashtra , India.
authors.forename: K G
authors.initials: KG
authors.lastname: Bothara
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000072198:ADAM17 Protein; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry* / Q000494:pharmacology; D002351:Carrageenan; D020134:Catalytic Domain; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D008297:Male; D020782:Matrix Metalloproteinases / Q000737:chemistry; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D002351:Carrageenan; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein; C000606464:Adam17 protein, rat
keywords: MMPs; TACE; glide; induced fit docking (IFD); sulfonamide