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Open AccessArticle

SAR by Space: Enriching Hit Sets from the Chemical Space

BioSolveIT GmbH, An der Ziegelei 79, 53757 Sankt Augustin, Germany
Enamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, Ukraine
Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Kyiv, Ukraine
Bienta/Enamine Ltd., Chervonotkatska Street 78, 02094 Kyiv, Ukraine
Chemspace, Ilukstes iela 38-5, LV-1082 Riga, Latvia
Authors to whom correspondence should be addressed.
Academic Editors: Diego Muñoz-Torrero, F. Javier Luque and Marçal Pastor-Anglada
Molecules 2019, 24(17), 3096;
Received: 26 July 2019 / Revised: 14 August 2019 / Accepted: 23 August 2019 / Published: 26 August 2019
(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)
We introduce SAR by Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolar hits have been identified and verified within less than six weeks, including the measurement of IC50 values. We conclude that this procedure is a substantial time-saver, accelerating both ligand and structure-based approaches in hit generation and lead optimization stages. View Full-Text
Keywords: chemical space; bromodomains; BRD4 inhibitors; new chemical entities chemical space; bromodomains; BRD4 inhibitors; new chemical entities
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Klingler, F.-M.; Gastreich, M.; Grygorenko, O.O.; Savych, O.; Borysko, P.; Griniukova, A.; Gubina, K.E.; Lemmen, C.; Moroz, Y.S. SAR by Space: Enriching Hit Sets from the Chemical Space. Molecules 2019, 24, 3096.

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