Structure‐based virtual screening of novel chitin synthase inhibitors for the control of Phytophthora sojae

Abstract BACKGROUND Chitin synthase (CHS) is an important target for pesticide development as chitin biosynthesis is essential for the survival and reproduction of various organisms, such as oomycetes, fungi and insects. Small‐molecule inhibitors of CHS have potential applications for the control of agricultural pests and diseases. RESULTS In this study, exploiting the cryo‐EM structures of Ps Chs1, the CHS indispensable to the sporangial production and virulence of soybean root rot pathogenic oomycete Phytophthora sojae , a virtual screening method combining by molecular docking, inhibitory activity measurement and biological activity determination was conducted, to identify novel small‐molecule inhibitors of CHS. A chemical library containing ≈1.8 million compounds was screened, and four potent inhibitors (HS‐20, HS‐24, HS‐36 and HS‐40) were identified. Amongst these compounds, HS‐20 showed the most potent inhibitory activity with a K i value of 4.2 ± 0.2 μM. Besides inhibitory activities towards Ps Chs1, these compounds were effective in decreasing sporangial production and preventing zoospore infection. When inoculated with zoospores, HS‐20 and HS‐24 completely inhibited the growth of P. sojae , suggesting their potential in its prevention and control. CONCLUSION This study identified four new compounds with potent chitin synthase (CHS) inhibitory activity, all of which significantly reduce sporangia production and zoospore infection. It also presents promising in silico techniques and small molecule candidates for the design and development of novel CHS inhibitors. © 2024 Society of Chemical Industry.