Pocket-based Lead Optimization Strategy for the Design and Synthesis of Chitinase Inhibitors

Abstract

Insect chitinases play an indispensable role in shedding old cuticle during molting. Targeting chitinase inhibition is a promising pest control strategy. Of ChtI, a chitinase from the destructive insect pest Ostrinia furnacalis (Asian corn borer), has been suggested as a potential target for designing green pesticides. A 4,5,6,7-tetrahydrobenzo­[b]­thiophene-3-carboxylate scaffold was previously obtained, and further derivatization generated the lead compound 1 as Of ChtI inhibitor. Here, based on the predicted binding mode of compound 1, the pocket-based lead optimization strategy was applied. A series of analogues was synthesized, and their inhibitory activities against Of ChtI were evaluated. Compound 8 with 6-tert-pentyl showed preferential inhibitory activity with a K i value of 0.71 μM. Their structure–activity relationships suggested that the compound with larger steric hindrance at the 6-nonpolar group was essential for inhibitory activity due to its stronger interactions with surrounding amino acids. This work provides a strategy for designing potential chitinase inhibitors.

Development of Novel Pesticides Targeting Insect Chitinases: A Minireview and Perspective

“…Furthermore, a pocket-based lead optimization based on compound 11 was performed, and several compounds with improved inhibitory activity were obtained. 29 Among them, compound 12 with a 6-tert-pentyl substituent inhibited Of ChtI, with a K i value of 0.71 μM. The binding mode of compound 12 is similar to the mode observed in compound 11, but the larger steric hindrance at the 6nonpolar group of compound 12 enhanced interactions with the surrounding amino acids.…”

“…Molecular docking studies revealed that they occupied subsites from −3 to +1 via hydrophobic stacking interactions with aromatic residues, including Tyr30, Trp34, Phe61, Trp107, Tyr272, Phe309, and Trp372 (Figure D). Furthermore, a pocket-based lead optimization based on compound 11 was performed, and several compounds with improved inhibitory activity were obtained . Among them, compound 12 with a 6- tert -pentyl substituent inhibited Of ChtI, with a K i value of 0.71 μM.…”

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 ].…”

“…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.…”

Structure-based virtual screening of highly potent inhibitors of the nematode chitinase CeCht1

“…The scarce nematode chitinase inhibitors may be, to a great extent, attributed to the lagged research on the structure of nematode chitinases. The availability of structure information could facilitate both structure-based virtual screening for inhibitor development and elucidation of inhibitory mechanism for inhibitor optimization [24][25][26][27] . Recently, we resolved the crystal structure of CeCht1 (PDB ID: 6LDU), a chitinase from the model nematode C. elegans 28 .…”