Scytalone dehydratase inhibitors

Scytalone Dehydratase Inhibitors via a focused mixture strategy... 

Table 20.3 Structures of inhibitors of scytalone dehydratase (SD) in DHN melanin biosynthesis.

Biochemical Reaction Mechanism of Scytalone Dehydratase and Structure-based Inhibitor Design... 

Scytalone dehydratase catalyzes two analogous steps in DHN melanin biosynthesis (Fig. 20.1). Various biochemical aspects of the catalysis have been investigated by Douglas Jordan and coworkers from DuPont [Basarab et al., 2002 Zheng et al, 2002 Jordan et al, 2000 a Jordan et al., 2000 b Basarab et al., 1999 Jordan et al, 1999]. Based on crystal structure analysis, which is discussed below in much more detail with respect to inhibitor design, a biochemical reaction mechanism can be proposed (Fig. 20.3). 

From published protein X-ray structures of scytalone dehydratase (SD) in its apo form and co-crystallized with several inhibitors (Table 20.4), its binding niche in the presence of inhibitors is rather well known. Protein X-ray structures with the natural substrates scytalone or vermelone, which are considerably smaller in size than the inhibitors, are not available. 

Chen, JA4., Xu, S.L., Wawrzak, Z., Basarab, G.S., and Jordan, D.B. (1998) Structure-based design of potent inhibitors of scytalone dehydratase displacement of a water molecule from the active site. Biochemistry, 37,17735 17744. 

Although we have accumulated a lot of experience since the practical problem of fungicide resistance first occurred in the early 1970 s, the recent outbreaks of resistance to Qols and MBI-Ds (melanin biosynthesis inhibitors, vAiich target scytalone dehydratase) demonstrated how resistance management is still difficult to achieve. 

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