De Novo Fragment Design for Drug Discovery and Chemical Biology.
Automated molecular de novo design led to the discovery of an innovative inhibitor of death-associated protein kinase 3 (DAPK3). An unprecedented crystal structure of the inactive DAPK3 homodimer shows the fragment-like hit bound to the ATP pocket. Target prediction software based on machine learning models correctly identified additional macromolecular targets of the computationally designed compound and the structurally related marketed drug azosemide. The study validates computational de novo design as a prime method for generating chemical probes and starting points for drug discovery.
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
Tiago
T
Rodrigues
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
Daniel
D
Reker
SARomics Biostructures AB, Medicon Village, 22381 Lund (Sweden).
Martin
M
Welin
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
Michael
M
Caldera
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
Cyrill
C
Brunner
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
Gisela
G
Gabernet
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland).
Petra
P
Schneider
SARomics Biostructures AB, Medicon Village, 22381 Lund (Sweden).
Björn
B
Walse
Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland). gisbert.schneider@pharma.ethz.ch.
Gisbert
G
Schneider
D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases
chemical biology; computational chemistry; kinases; molecular design; target prediction