Identification of novel antifeedant aphicides through in silico screening of inward rectifier potassium channel inhibitors

The cotton aphid Aphis gossypii is responsible of the transmission of nonpersistent Sweet potato feathery mottle virus (SPFMV) which synergizes with whitefly-vectored semipersistent Sweet potato chlorotic stunt virus (SPCSV) to engender the Sweet potato virus disease (SPVD). Up to 90% loss in sweet potato production has been reported due to this disease complex and importantly, inoculation of SPFMV can occur within seconds to minutes after the aphid landed on the plant. Currently, no commercialized chemical is available that is capable of inducing mortality or preventing feeding prior to pathogen transmission. Inward rectifier potassium (Kir) channels regulate salivary gland function in hemipteran insects and previous work has shown exposure of aphids to Kir channel inhibitors prevents plant feeding. Thus, the goal of this study was to discover novel chemical inhibitors of aphid Kir channels through AI-assisted docking simulations against the A. gossypii Kir1 and screening virtual chemical libraries. Over 100 compounds being single nanomolar inhibitors for aphid Kir channel were identified via in silico screen based on in silico binding affinities. Electrical penetration graph (EPG) techniques were performed to validate antifeedant activity of these inhibitors and select molecules show statistically significant (P< 0.05) reduction of probing and feeding behavior when compared to control. For example, KI-3 reduced the secretory activity of the salivary gland by approximately 80% compared to control and reduced the number of aphids that initiated probe by 79%. These data suggest AI-assisted docking simulations are capable of identifying potent Kir channel inhibitors with select compounds maintaining vivo antifeedant activity.