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Merging Allosteric and Active Site Binding Motifs: De novo Generation of Target Selectivity and Potency via Natural‐Product‐Derived Fragments
Author(s) -
Lanz Jan,
Riedl Rainer
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402478
Subject(s) - allosteric regulation , natural product , benzoic acid , chemistry , chemical biology , drug discovery , stereochemistry , small molecule , binding site , ligand (biochemistry) , active site , combinatorial chemistry , biochemistry , receptor , enzyme
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 IC 50 values of 11 n M ( 3 : LE=0.35) and 6 n M ( 4 : LE=0.31).