TY  - JOUR
A1  - Friedrich, Lukas
A1  - Cingolani, Gino
A1  - Ko, Ying-Hui
A1  - Iaselli, Mariaclara
A1  - Miciaccia, Morena
A1  - Perrone, Maria Grazia
A1  - Neukirch, Konstantin
A1  - Bobinger, Veronika
A1  - Merk, Daniel
A1  - Hofstetter, Robert Klaus
A1  - Werz, Oliver
A1  - Koeberle, Andreas
A1  - Scilimati, Antonio
A1  - Schneider, Gisbert
T1  - Learning from nature: from a marine natural product to synthetic cyclooxygenase-1 inhibitors by automated de novo design
T2  - Advanced science
N2  - The repertoire of natural products offers tremendous opportunities for chemical biology and drug discovery. Natural product-inspired synthetic molecules represent an ecologically and economically sustainable alternative to the direct utilization of natural products. De novo design with machine intelligence bridges the gap between the worlds of bioactive natural products and synthetic molecules. On employing the compound Marinopyrrole A from marine Streptomyces as a design template, the algorithm constructs innovative small molecules that can be synthesized in three steps, following the computationally suggested synthesis route. Computational activity prediction reveals cyclooxygenase (COX) as a putative target of both Marinopyrrole A and the de novo designs. The molecular designs are experimentally confirmed as selective COX-1 inhibitors with nanomolar potency. X-ray structure analysis reveals the binding of the most selective compound to COX-1. This molecular design approach provides a blueprint for natural product-inspired hit and lead identification for drug discovery with machine intelligence.
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/63985
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-639855
SN  - 2198-3844
N1  - This work was financially supported by ETH RETHINK initiative and a Novartis FreeNovation grant AI in Drug Discovery (to G.S.), the NIH grants R01 GM100888, S10 OD017987, S10 OD023479 (to G.C.), and Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project number 316213987, SFB 1278 PolyTarget (projects A04, C02; to O.W.) and project number 239748522, SFB 1127 ChemBioSys (project A04; to O.W.).
N1  - Data Availability Statement

PDB-ID: 7JXT. Protein Data Bank: www.pdb.org.
VL  - 8
IS  - 16, art. 2100832
SP  - 1
EP  - 12
PB  - Wiley-VCH
CY  - Weinheim
ER  -