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Recovering actives in multi-antitarget and target design of analogs of the myosin II inhibitor blebbistatin

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Abstract
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 silica methods for understanding and reliably predicting these pharmacological outcomes In this paper, we have evaluated the potential of several in silica 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.
Keywords
blebbistatin, fingerprint, ECFP, multitarget, antitarget, myosin II, ATPase, motility, MODIFIED (S)-BLEBBISTATIN ANALOGS, CRYSTAL-STRUCTURE, GENETIC ALGORITHM, TOOL PROPERTIES, CANCER-CELLS, BLUE-LIGHT, INSIGHTS, DOCKING, COMPLEX, SPECIFICITY

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Chicago
Roman, Bart, Rita C Guedes, Christian Stevens, and Alfonso T García-Sosa. 2018. “Recovering Actives in Multi-antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin.” Frontiers in Chemistry 6.
APA
Roman, B., Guedes, R. C., Stevens, C., & García-Sosa, A. T. (2018). Recovering actives in multi-antitarget and target design of analogs of the myosin II inhibitor blebbistatin. FRONTIERS IN CHEMISTRY, 6.
Vancouver
1.
Roman B, Guedes RC, Stevens C, García-Sosa AT. Recovering actives in multi-antitarget and target design of analogs of the myosin II inhibitor blebbistatin. FRONTIERS IN CHEMISTRY. 2018;6.
MLA
Roman, Bart, Rita C Guedes, Christian Stevens, et al. “Recovering Actives in Multi-antitarget and Target Design of Analogs of the Myosin II Inhibitor Blebbistatin.” FRONTIERS IN CHEMISTRY 6 (2018): n. pag. Print.
@article{8565152,
  abstract     = {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 silica methods for understanding and reliably predicting these pharmacological outcomes In this paper, we have evaluated the potential of several in silica 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.},
  articleno    = {179},
  author       = {Roman, Bart and Guedes, Rita C and Stevens, Christian and Garc{\'i}a-Sosa, Alfonso T},
  issn         = {2296-2646},
  journal      = {FRONTIERS IN CHEMISTRY},
  language     = {eng},
  pages        = {12},
  title        = {Recovering actives in multi-antitarget and target design of analogs of the myosin II inhibitor blebbistatin},
  url          = {http://dx.doi.org/10.3389/fchem.2018.00179},
  volume       = {6},
  year         = {2018},
}

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