Virtual screening, synthesis, and bioactivity evaluation for the discovery of β‐N‐acetyl‐D‐hexosaminidase inhibitors

Abstract

BACKGROUNDMolting is an essential insect developmental process, in which a variety of enzymes are involved. The inhibition of these enzymes effect normal insect growth and development and may even cause death. OfHex1, one of the β‐N‐acetyl‐D‐hexosaminidases, is a key enzyme involved in the molting process of the Asian corn borer (Ostrinia furnacalis), and is deemed a potential insecticidal target.RESULTSBased on the crystal structure of OfHex1, virtual screening was carried out to obtain a novel class of OfHex1 inhibitors, of which, 28 compounds were subjected to bioactivity evaluation. The compound 3, N‐(3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophen‐2‐yl)benzamide, showed good inhibition against OfHex1 with a Ki value of 11.2 μM. Structure optimization and molecular docking were applied for the structure–activity relationship analysis. The results also showed that the cyano group of this compound was essential for the maintenance of its inhibitory activity against OfHex1. Additionally, the interaction between this compound and Trp490, Glu328, Tyr475 and Trp524 were important for inhibitory activity.CONCLUSIONThe advantages of the derivatives of 2‐amino‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile, which have simple chemical structures and are easily synthesized, suggests them to be developed further as potential OfHex1 inhibitors for pest control. © 2020 Society of Chemical Industry

The Role of Chitooligosaccharidolytic β-N-Acetylglucosamindase in the Molting and Wing Development of the Silkworm Bombyx mori

“…If chitin digestion and degradation in the old cuticle are hindered, insect growth and development will be blocked [ 10 ]. The key genes that affect insect molting are potential insect control targets [ 6 , 7 , 44 ]. HEXs are enzymes involved in chitin catabolism during insect growth [ 30 ].…”

“…Some HEXs inhibitors have been uncovered via structure-based virtual screening [ 7 , 38 , 52 , 53 , 54 ] but they are all based on the crystal structure information of OfHex1. This is because the OfHex1 of O. furnacalis is the only insect-derived HEX with crystal structure information.…”

“…Crop pests pose a serious challenge to agricultural production and food security [ 1 , 2 ]. As such, target-based insecticides have high specificity and safety to non-target organisms and the environment; thus, they have attracted considerable attention [ 3 , 4 , 5 , 6 , 7 , 8 ]. Chitin is a long-chain polymer of N -acetylglucosamine that is present in many insect tissues including the epidermis, integument, trachea, salivary gland, and intestinal peritrophic membrane.…”

Are insect GPCRs ideal next‐generation pesticides: opportunities and challenges

“…In a similar study by da Costa et al [103], organophosphorus compounds were selected with similar methodology and potential inhibitors of acetylcholinesterase enzymes and juvenile hormone protein were identified. Targeting OfHex1, one of the β-N-acetyl-D-hexosaminidases with a crucial effect on molting, Dong et al have utilized virtual screening to find novel inhibitors that can be used as insecticides [104].…”

“…Targeting Of Hex1, one of the β‐ N ‐acetyl‐ d ‐hexosaminidases with a crucial effect on molting, Dong et al . [104] have utilized virtual screening to find novel inhibitors that can be used as insecticides.…”