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Title: Merging allosteric and active site binding motifs : de novo generation of target selectivity and potency via natural-product-derived fragments
Authors : Lanz, Jan
Riedl, Rainer
Published in : ChemMedChem
Volume(Issue) : 10
Issue : 3
Pages : 451
Pages to: 454
Publisher / Ed. Institution : Wiley
Issue Date: 2015
License (according to publishing contract) : CC BY-NC-ND 4.0: Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International
Type of review: Peer review (Publication)
Language : English
Subjects : Medicinal chemistry; De novo drug design
Subject (DDC) : 572: Biochemistry
615: Pharmacology and therapeutics
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).
Departement: Life Sciences und Facility Management
Publication type: Article in scientific Journal
DOI : 10.1002/cmdc.201402478
ISSN: 1860-7187
Appears in Collections:Publikationen Life Sciences und Facility Management

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