title: Merging allosteric and active site binding motifs: de novo generation of target selectivity and potency via natural-product-derived fragments.
abstract: The de novo design of molecules from scratch with tailored biological activity is still the major intellectual challenge in chemical biology and drug discovery. Herein we validate natural-product-derived fragments (NPDFs) as excellent molecular seeds for the targeted de novo discovery of lead structures for the modulation of therapeutically relevant proteins. The application of this de novo approach delivered, in synergy with the combination of allosteric and active site binding motifs, highly selective and ligand-efficient non-zinc-binding (3: 4-{[5-(2-{[(3-methoxyphenyl)methyl]carbamoyl}eth-1-yn-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]methyl}benzoic acid) as well as zinc-binding (4: 4-({5-[2-({[3-(3-carboxypropoxy)phenyl]methyl}carbamoyl)eth-1-yn-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzoic acid) uracil-based MMP-13 inhibitors presenting IC50 values of 11 nM (3: LE=0.35) and 6 nM (4: LE=0.31).
authors.affiliation: Institute for Chemistry and Biological Chemistry, Zurich University of Applied Sciences, Einsiedlerstrasse 31, 8820 Wädenswil (Switzerland) www.icbc.zhaw.ch/organic-chemistry.
authors.forename: Jan
authors.initials: J
authors.lastname: Lanz
authors.forename: Rainer
authors.initials: R
authors.lastname: Riedl
mesh_terms: D000495:Allosteric Site; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13
keywords: de novo drug design; enzyme inhibitors; fragment-based drug discovery; natural products; structure-activity relationships; water-mediated interactions