Optimizing TRPM4 inhibitors in the MHFP6 chemical space.
Chemical space
Cheminformatics
Ion channels
Structure-activity relationships
Virtual screening
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Mar 2019
15 Mar 2019
Historique:
received:
24
10
2018
revised:
18
12
2018
accepted:
19
01
2019
pubmed:
2
2
2019
medline:
6
3
2019
entrez:
2
2
2019
Statut:
ppublish
Résumé
We recently reported 4-chloro-2-(2-chlorophenoxy)acetamido)benzoic acid (CBA) as the first potent inhibitor of TRPM4, a cation channel implicated in cardiac diseases and prostate cancer. Herein we report a structure-activity relationship (SAR) study of CBA resulting in two new potent analogs. To design and interpret our SAR we used interactive color-coded 3D-maps representing similarities between compounds calculated with MHFP6 (MinHash fingerprint up to six bonds), a new molecular fingerprint outperforming other fingerprints in benchmarking virtual screening studies. We further illustrate the general applicability of our method by visualizing the structural diversity of active compounds from benchmarking sets in relation to decoy molecules and to drugs. MHFP6 chemical space 3D-maps might be generally helpful in designing, interpreting and communicating the results of SAR studies. The modified WebMolCS is accessible at http://gdb.unibe.ch and the code is available at https://github.com/reymond-group/webMolCS for off-line use.
Identifiants
pubmed: 30708257
pii: S0223-5234(19)30060-1
doi: 10.1016/j.ejmech.2019.01.048
pii:
doi:
Substances chimiques
Benzoates
0
TRPM Cation Channels
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
167-177Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.