Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin
In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in sili...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2018.00179/full |
| _version_ | 1818518702667071488 |
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| author | Bart I. Roman Bart I. Roman Rita C. Guedes Christian V. Stevens Christian V. Stevens Alfonso T. García-Sosa |
| author_facet | Bart I. Roman Bart I. Roman Rita C. Guedes Christian V. Stevens Christian V. Stevens Alfonso T. García-Sosa |
| author_sort | Bart I. Roman |
| collection | DOAJ |
| description | In multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of (S)-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof. Standard and augmented structure-based design techniques could not recover the observed activity profiles. A ligand-based method using molecular fingerprints was, however, able to select actives for myosin II inhibition. Using further ligand- and structure-based methods, we also evaluated toxicity through androgen receptor binding, affinity for an array of antitargets and the ADME profile (including assay-interfering compounds) of the series. In conclusion, in the search for (S)-blebbistatin analogs, the dissimilarity distance of molecular fingerprints to known actives and the computed antitarget and physicochemical profile of the molecules can be used for compound design for molecules with potential as tools for modulating myosin II and motility-related diseases. |
| first_indexed | 2024-12-11T01:13:55Z |
| format | Article |
| id | doaj.art-998163fdb7f7460d8ebabe15dc9c9980 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-11T01:13:55Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-998163fdb7f7460d8ebabe15dc9c99802022-12-22T01:25:57ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462018-05-01610.3389/fchem.2018.00179369165Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor BlebbistatinBart I. Roman0Bart I. Roman1Rita C. Guedes2Christian V. Stevens3Christian V. Stevens4Alfonso T. García-Sosa5Research Group SynBioC, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent UniversityGhent, BelgiumCancer Research Institute GhentGhent, BelgiumDepartment of Medicinal Chemistry, Faculty of Pharmacy, Research Institute for Medicines (iMed.ULisboa), Universidade de LisboaLisbon, PortugalResearch Group SynBioC, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent UniversityGhent, BelgiumCancer Research Institute GhentGhent, BelgiumDepartment of Molecular Technology, Institute of Chemistry, University of TartuTartu, EstoniaIn multitarget drug design, it is critical to identify active and inactive compounds against a variety of targets and antitargets. Multitarget strategies thus test the limits of available technology, be that in screening large databases of compounds vs. a large number of targets, or in using in silico methods for understanding and reliably predicting these pharmacological outcomes. In this paper, we have evaluated the potential of several in silico approaches to predict the target, antitarget and physicochemical profile of (S)-blebbistatin, the best-known myosin II ATPase inhibitor, and a series of analogs thereof. Standard and augmented structure-based design techniques could not recover the observed activity profiles. A ligand-based method using molecular fingerprints was, however, able to select actives for myosin II inhibition. Using further ligand- and structure-based methods, we also evaluated toxicity through androgen receptor binding, affinity for an array of antitargets and the ADME profile (including assay-interfering compounds) of the series. In conclusion, in the search for (S)-blebbistatin analogs, the dissimilarity distance of molecular fingerprints to known actives and the computed antitarget and physicochemical profile of the molecules can be used for compound design for molecules with potential as tools for modulating myosin II and motility-related diseases.https://www.frontiersin.org/article/10.3389/fchem.2018.00179/fullblebbistatinfingerprintECFPmultitargetantitargetmyosin II |
| spellingShingle | Bart I. Roman Bart I. Roman Rita C. Guedes Christian V. Stevens Christian V. Stevens Alfonso T. García-Sosa Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin Frontiers in Chemistry blebbistatin fingerprint ECFP multitarget antitarget myosin II |
| title | Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin |
| title_full | Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin |
| title_fullStr | Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin |
| title_full_unstemmed | Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin |
| title_short | Recovering Actives in Multi-Antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin |
| title_sort | recovering actives in multi antitarget and target design of analogs of the myosin ii inhibitor blebbistatin |
| topic | blebbistatin fingerprint ECFP multitarget antitarget myosin II |
| url | https://www.frontiersin.org/article/10.3389/fchem.2018.00179/full |
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