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De Novo Fragment Design for Drug Discovery and Chemical Biology
Author(s) -
Rodrigues Tiago,
Reker Daniel,
Welin Martin,
Caldera Michael,
Brunner Cyrill,
Gabernet Gisela,
Schneider Petra,
Walse Björn,
Schneider Gisbert
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201508055
Subject(s) - drug discovery , fragment (logic) , computational biology , chemical biology , drug , computer science , structural biology , chemistry , biology , biochemistry , algorithm , pharmacology
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.