The small molecule blebbistatin is now a front line tool in the study of myosin function. Chemical modi. cation of the tricyclic core of blebbistatin could deliver the next generation of myosin inhibitors and to help address this we report here on the impact of structural changes in the methyl-substituted aromatic ring of blebbistatin on its biological activity. Chemical methods for the preparation of isomeric methyl-containing analogues are reported and a series of co-crystal structures are used to rationalise the observed variations in their biological activity. These studies further support the view that the previously identified binding mode of blebbistatin to Dictyostelium discoideum myosin II is of relevance to its mode of action. A discussion of the role that these observations have on planning the synthesis of focused libraries of blebbistatin analogues is also provided including an assessment of possibilities by computational methods. These studies are ultimately directed at the development of novel myosin inhibitors with improved affinity and different selectivity profiles from blebbistatin itself.
AB -The small molecule blebbistatin is now a front line tool in the study of myosin function. Chemical modi. cation of the tricyclic core of blebbistatin could deliver the next generation of myosin inhibitors and to help address this we report here on the impact of structural changes in the methyl-substituted aromatic ring of blebbistatin on its biological activity. Chemical methods for the preparation of isomeric methyl-containing analogues are reported and a series of co-crystal structures are used to rationalise the observed variations in their biological activity. These studies further support the view that the previously identified binding mode of blebbistatin to Dictyostelium discoideum myosin II is of relevance to its mode of action. A discussion of the role that these observations have on planning the synthesis of focused libraries of blebbistatin analogues is also provided including an assessment of possibilities by computational methods. These studies are ultimately directed at the development of novel myosin inhibitors with improved affinity and different selectivity profiles from blebbistatin itself.
KW - BLEBBISTATIN INHIBITION KW - MOTOR DOMAIN KW - CONTRACTILE RING KW - II INHIBITOR KW - CYTOKINESIS KW - MECHANISM KW - CELLS KW - SPECIFICITY KW - KINASE KW - ACTIN U2 - 10.1039/b801223g DO - 10.1039/b801223g M1 - Article JO - Organic and Biomolecular Chemistry JF - Organic and Biomolecular Chemistry SN - 1477-0520 IS - 12 VL - 6 SP - 2076 EP - 2084 ER -