Small-molecule inhibitors of myosin proteins

Abstract

Advances in screening and computational methods have enhanced recent efforts to discover/design small-molecule protein inhibitors. One attractive target for inhibition is the myosin family of motor proteins. Myosins function in a wide variety of cellular processes, from intracellular trafficking to cell motility, and are implicated in several human diseases (e.g., cancer, hypertrophic cardiomyopathy, deafness and many neurological disorders). Potent and selective myosin inhibitors are, therefore, not only a tool for understanding myosin function, but are also a resource for developing treatments for diseases involving myosin dysfunction or overactivity. This review will provide a brief overview of the characteristics and scientific/therapeutic applications of the presently identified small-molecule myosin inhibitors before discussing the future of myosin inhibitor and activator design.

Figure 1. Mechanisms of small-molecule inhibition of myosin ATPase

All myosins move or translocate along actin filaments using energy gained from ATP hydrolysis by an actin-activated Mg²⁺ ATPase. This process occurs in a series of discrete steps and the presently identified myosin inhibitors are characterized by their ability to hinder specific steps. As an overview, the binding of ATP to an actomyosin complex (A) results in dissociation of myosin from actin. ATP is then hydrolyzed to form ADP and inorganic phosphate (Pi) and the motor domain is repositioned into a ‘cocked’ state (B). The myosin–ADP–Pi complex rebinds actin and releases the inorganic phosphate, triggering a ‘power stroke’ of directed myosin (or actin) movement (C). Lastly, the ADP is released (D), leaving a new actomyosin complex [24,25]. All of the presently characterized myosin II inhibitors (blebbistatin, N-benzyl-p-toluene sulphonamide, 2,3-Butanedione monoxime) operate by hindering Pi release during (C) and BTS also hinders ADP release during (D). The myosin V inhibitor Myo-Vin1 hinders ADP release during (D). The myosin V inhibitor pentabromopseudilin has a more global effect on ATPase dynamics, as it has been shown to decrease ATP binding rates (A), ATP hydrolysis rates (B) and ADP dissociation rates (D), as well as reduce the coupling between the actin and nucleotide binding sites in the myosin motor domain (Between [C] and [D]). The myosin I inhibitor pentachloropseudilin also reduces the coupling between the actin and nucleotide binding sites in the motor domain (between [C] and [D]). BDM: 2,3-Butanedione monoxime; BTS: N-benzyl-p-toluene sulphonamide; PBP: Pentabromopseudilin; PCIP: Pentachloropseudilin; Pi: Inorganic phosphate.