Strategy for generation of new TACE inhibitors: pharmacophore and counter pharmacophore modeling to remove non-selective hits

Abstract

Present study describes the ligand-based molecular modeling along with virtual screening (VS) approach for generation of new tumor necrosis factor-a converting enzyme (TACE) inhibitors. In ligand-based molecular modeling, two statistically reliable HipHop pharmacophore models Hip1 and counter pharmacophore (CP1) were generated using training set of 3 and 2 molecules, respectively. CP1 was generated using inhibitors of MMP-1 (matrix metalloproteinase-1), an important enzyme involved in musculoskeletal degradation. VS was performed with model Hip1 in in-house database of 1.2 million molecules. In addition, the retrieved molecules were screened with CP1. The combination of both models helped for generating new improved TACE inhibitor molecules.

Σύνθεση Και Μελέτη Αναστολέων Λιπολυτικών Ενζύμων

“…Δίκαζ οπεφεοκεξ βζα ηδκ μλείδςζδ ηςκ θζπανχκ μλέςκ πμο πανάβμοκ θεοημηνζέκζα ηαζ μζ θζπμλίκεξ250 ηαζ ιπμνμφκ επίζδξ κα απεκενβμπμζδεμφκ απυ ηα οδνμλαιζηά μλέα.Ο δζαθοηυξ TNF-α είκαζ οπεφεοκμξ βζα θθεβιμκχδεζξ ακηζδνάζεζξ πμο ζοκδέμκηαζ ιε δζάθμνεξ αζεέκεζεξ, υπςξ δ θθεβιμκχδδξ κυζμξ ημο εκηένμο, δ νεοιαημεζδήξ ανενίηζδα, δ μζηεμανενίηζδα, ημ εβηεθαθζηυ επεζζυδζμ ηαζ δ κυζμξ ημο Crohn. Ζ δζαθοηή αοηή ιμνθή πνμένπεηαζ απυ ημκ ΣΝF-α ιε ηδ αμήεεζα ημο ιεηαηνεπηζημφ εκγφιμο ημο TNF-α,251 ημ μπμίμ είκαζ ιία ιεηαθθμπνςηεάζδ ιε εκενβυ ηέκηνμ πανυιμζμ ιε αοηυ ηςκ MMPs. CTCL)266 ηαζ κα δμηζιάγεηαζ ηαζ βζα άθθεξ ηαημήεεζεξ 267.…”