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Successive Statisti...
Successive Statistical and Structure-Based Modeling to Identify Chemically Novel Kinase Inhibitors
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- Burggraaff, Lindsey (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- Lenselink, Eelke B. (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- Jespers, Willem (författare)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- van Engelen, Jesper (författare)
- Leiden Univ, Leiden Inst Adv Comp Sci, Dept Comp Sci, NL-2333 CA Leiden, Netherlands.
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- Bongers, Brandon J. (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- Gonzalez, Marina Gorostiola (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- Liu, Rongfang (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- Hoos, Holger H. (författare)
- Leiden Univ, Leiden Inst Adv Comp Sci, Dept Comp Sci, NL-2333 CA Leiden, Netherlands.
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- van Vlijmen, Herman W. T. (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.;Janssen Res & Dev, B-2340 Beerse, Belgium.
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- IJzerman, Adriaan P. (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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- van Westen, Gerard J. P. (författare)
- Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands.
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Leiden Univ, Leiden Acad Ctr Drug Res, Div Drug Discovery & Safety, NL-2333 CC Leiden, Netherlands Beräkningsbiologi och bioinformatik (creator_code:org_t)
- 2020-04-28
- 2020
- Engelska.
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Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 60:9, s. 4283-4295
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Abstract
Ämnesord
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- Kinases are frequently studied in the context of anticancer drugs. Their involvement in cell responses, such as proliferation, differentiation, and apoptosis, makes them interesting subjects in multitarget drug design. In this study, a workflow is presented that models the bioactivity spectra for two panels of kinases: (1) inhibition of RET, BRAF, SRC, and S6K, while avoiding inhibition of MKNK1, TTK, ERK8, PDK1, and PAK3, and (2) inhibition of AURKA, PAK1, FGFR1, and LKB1, while avoiding inhibition of PAK3, TAK1, and PIK3CA. Both statistical and structure-based models were included, which were thoroughly benchmarked and optimized. A virtual screening was performed to test the workflow for one of the main targets, RET kinase. This resulted in 5 novel and chemically dissimilar RET inhibitors with remaining RET activity of <60% (at a concentration of 10 mu M) and similarities with known RET inhibitors from 0.18 to 0.29 (Tanimoto, ECFP6). The four more potent inhibitors were assessed in a concentration range and proved to be modestly active with a pIC(50) value of 5.1 for the most active compound. The experimental validation of inhibitors for RET strongly indicates that the multitarget workflow is able to detect novel inhibitors for kinases, and hence, this workflow can potentially be applied in polypharmacology modeling. We conclude that this approach can identify new chemical matter for existing targets. Moreover, this workflow can easily be applied to other targets as well.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
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Burggraaff, Lind ...
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Lenselink, Eelke ...
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Jespers, Willem
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van Engelen, Jes ...
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Bongers, Brandon ...
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Gonzalez, Marina ...
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Liu, Rongfang
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Hoos, Holger H.
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van Vlijmen, Her ...
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IJzerman, Adriaa ...
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van Westen, Gera ...
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