Key result
Ligand-based methods using extended connectivity fingerprints successfully correlated with experimental myosin II ATPase inhibitory activity, whereas standard structure-based docking methods failed.
Ligand-based molecular fingerprinting is superior to standard structure-based docking for predicting the myosin II inhibitory activity of blebbistatin analogs, providing a framework for future drug design.
Ligand-based fingerprinting may prioritize blebbistatin analogs for testing; leaves open prospective validation versus docking.
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 versus 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.
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Roman et al. (2018) studied Myosin II inhibition (n=19). Blebbistatin analogs was evaluated on Prediction of active compounds (IC50 < 10 µM) using in silico methods. Ligand-based methods using extended connectivity fingerprints successfully correlated with experimental myosin II ATPase inhibitory activity, whereas standard structure-based docking methods failed.
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