Premium
In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB
Author(s) -
Hrast Martina,
Jukič Marko,
Patin Delphine,
Tod Julie,
Dowson Christopher G.,
Roper David I.,
Barreteau Hélène,
Gobec Stanislav
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13172
Subject(s) - pharmacophore , in silico , virtual screening , chemistry , context (archaeology) , tetrazole , peptidoglycan , combinatorial chemistry , stereochemistry , computational biology , chemical space , drug discovery , ligand (biochemistry) , enzyme , biochemistry , biology , receptor , paleontology , gene
In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP‐ N ‐acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP + , a pharmacophore model was generated and used in a virtual screening campaign with combined structure‐based and ligand‐based approaches. To explore chemical space around hit compounds, further similarity search and organic synthesis were employed to obtain several compounds with micromolar IC 50 values on MurB. The best inhibitors in the reported series of 5‐substituted tetrazol‐2‐yl acetamides were compounds 13 , 26 and 30 with IC 50 values of 34, 28 and 25 μ m , respectively. None of the reported compounds possessed in vitro antimicrobial activity against Staphylococcus aureus and Escherichia coli .