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Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space
Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden..
Stockholm Univ, Dept Biochem & Biophys, SE-10691 Stockholm, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Box 1031, SE-17121 Solna, Sweden..
Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Box 1031, SE-17121 Solna, Sweden..
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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 19, p. 8160-8169Article in journal (Refereed) Published
Abstract [en]

Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 mu M. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2017. Vol. 60, no 19, p. 8160-8169
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-340139DOI: 10.1021/acs.jmedchem.7b01006ISI: 000413131400015PubMedID: 28929756OAI: oai:DiVA.org:uu-340139DiVA, id: diva2:1178392
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilAvailable from: 2018-01-29 Created: 2018-01-29 Last updated: 2018-01-29Bibliographically approved

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Carlsson, Jens

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