Historeceptomic fingerprints for drug-like compounds
Most drugs exert their beneficial and adverse effects through their combined action on several different molecular targets (polypharmacology). The true molecular fingerprint of the direct action of a drug has two components: the ensemble of all the receptors upon which a drug acts and their level of...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2015-12-01
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| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fphys.2015.00371/full |
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| author | Evgeny eShmelkov Arsen eGrigoryan James eSwetnam Junyang eXin Doreen eTivon Sergey eShmelkov Sergey eShmelkov Timothy eCardozo |
| author_facet | Evgeny eShmelkov Arsen eGrigoryan James eSwetnam Junyang eXin Doreen eTivon Sergey eShmelkov Sergey eShmelkov Timothy eCardozo |
| author_sort | Evgeny eShmelkov |
| collection | DOAJ |
| description | Most drugs exert their beneficial and adverse effects through their combined action on several different molecular targets (polypharmacology). The true molecular fingerprint of the direct action of a drug has two components: the ensemble of all the receptors upon which a drug acts and their level of expression in organs/tissues. Conversely, the fingerprint of the adverse effects of a drug may derive from its action in bystander tissues. The ensemble of targets is almost always only partially known. Here we describe an approach improving upon and integrating both components: in silico identification of a more comprehensive ensemble of targets for any drug weighted by the expression of those receptors in relevant tissues. Our system combines more than 300K experimentally determined bioactivity values from the ChEMBL database and 4.2 billion generated molecular docking scores. We integrated these scores with gene expression data for human receptors across a panel of human tissues to produce drug-specific tissue-receptor (historeceptomics) scores. A statistical model was designed to identify significant scores, which define an improved fingerprint representing the unique activity of any drug. These multi-dimensional historeceptomic fingerprints describe, in a novel, intuitive, and easy to interpret style, the holistic picture of the mechanism of any drug’s action. Valuable applications in drug discovery and personalized medicine, including the identification of molecular signatures for drugs with polypharmacologic modes of action, detection of tissue-specific adverse effects of drugs, matching molecular signatures of a disease to drugs, target identification for bioactive compounds with unknown receptors, and hypothesis generation for drug/compound phenotypes may be enabled by this approach. The system has been deployed at drugable.org for access through a user-friendly web site. |
| first_indexed | 2024-12-10T03:58:09Z |
| format | Article |
| id | doaj.art-baa35d410b4c4d7c95380d091417906e |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-10T03:58:09Z |
| publishDate | 2015-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-baa35d410b4c4d7c95380d091417906e2022-12-22T02:03:04ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2015-12-01610.3389/fphys.2015.00371165262Historeceptomic fingerprints for drug-like compoundsEvgeny eShmelkov0Arsen eGrigoryan1James eSwetnam2Junyang eXin3Doreen eTivon4Sergey eShmelkov5Sergey eShmelkov6Timothy eCardozo7NYU School of MedicineNYU School of MedicineGoogle Inc.NYU School of MedicineGeneCentrix Inc.NYU School of MedicineNYU School of MedicineNYU School of MedicineMost drugs exert their beneficial and adverse effects through their combined action on several different molecular targets (polypharmacology). The true molecular fingerprint of the direct action of a drug has two components: the ensemble of all the receptors upon which a drug acts and their level of expression in organs/tissues. Conversely, the fingerprint of the adverse effects of a drug may derive from its action in bystander tissues. The ensemble of targets is almost always only partially known. Here we describe an approach improving upon and integrating both components: in silico identification of a more comprehensive ensemble of targets for any drug weighted by the expression of those receptors in relevant tissues. Our system combines more than 300K experimentally determined bioactivity values from the ChEMBL database and 4.2 billion generated molecular docking scores. We integrated these scores with gene expression data for human receptors across a panel of human tissues to produce drug-specific tissue-receptor (historeceptomics) scores. A statistical model was designed to identify significant scores, which define an improved fingerprint representing the unique activity of any drug. These multi-dimensional historeceptomic fingerprints describe, in a novel, intuitive, and easy to interpret style, the holistic picture of the mechanism of any drug’s action. Valuable applications in drug discovery and personalized medicine, including the identification of molecular signatures for drugs with polypharmacologic modes of action, detection of tissue-specific adverse effects of drugs, matching molecular signatures of a disease to drugs, target identification for bioactive compounds with unknown receptors, and hypothesis generation for drug/compound phenotypes may be enabled by this approach. The system has been deployed at drugable.org for access through a user-friendly web site.http://journal.frontiersin.org/Journal/10.3389/fphys.2015.00371/fullGene ExpressionMolecular Docking Simulationpolypharmacologydrug targetMechanism of drug action |
| spellingShingle | Evgeny eShmelkov Arsen eGrigoryan James eSwetnam Junyang eXin Doreen eTivon Sergey eShmelkov Sergey eShmelkov Timothy eCardozo Historeceptomic fingerprints for drug-like compounds Frontiers in Physiology Gene Expression Molecular Docking Simulation polypharmacology drug target Mechanism of drug action |
| title | Historeceptomic fingerprints for drug-like compounds |
| title_full | Historeceptomic fingerprints for drug-like compounds |
| title_fullStr | Historeceptomic fingerprints for drug-like compounds |
| title_full_unstemmed | Historeceptomic fingerprints for drug-like compounds |
| title_short | Historeceptomic fingerprints for drug-like compounds |
| title_sort | historeceptomic fingerprints for drug like compounds |
| topic | Gene Expression Molecular Docking Simulation polypharmacology drug target Mechanism of drug action |
| url | http://journal.frontiersin.org/Journal/10.3389/fphys.2015.00371/full |
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