Abstract
Transketolase (TKL) plays a key role in plant photosynthesis and has been predicted to be a potent herbicide target. Homology modeling and molecular dynamics simulation were used to construct a target protein model. A target-based virtual screening was developed to discover novel potential transketolase inhibitors. Based on the receptor transketolase 1 and a target-based virtual screening combined with structural similarity, six new compounds were selected from the ZINC database. Among the structural leads, a new compound ZINC12007063 was identified as a novel inhibitor of weeds. Two novel series of carboxylic amide derivatives were synthesized, and their structures were rationally identified by NMR and HRMS. Biological evaluation of the herbicidal and antifungal activities indicated that the compounds 4u and 8h were the most potent herbicidal agents, and they also showed potent fungicidal activity with a relatively broad-spectrum. ZINC12007063 was identified as a lead compound of potential transketolase inhibitors, 4u and 8h which has the herbicidal and antifungal activities were synthesized based on ZINC12007063. This study lays a foundation for the discovery of new pesticides.
Highlights
Weed control in agricultural crops is a global problem
Since transketolase plays a key role in plant photosynthesis, and is highly conserved in plants, it represents an important candidate target for the development of new herbicides
Transketolase is a target for herbicide design [3,11], and it has a highly conserved homologous domain in higher plants and fungi
Summary
Weed control in agricultural crops is a global problem. Chemical control has become the best choice for weed control since the emergence of 2,4-dichlorophenoxyacetic acid (2,4-D) in the 1940s. With the advances in molecular biology and the widespread application of computer technology, the combination of computer simulation, chemical synthesis and biological testing represents has been became a new strategy for drug development. Since transketolase plays a key role in plant photosynthesis, and is highly conserved in plants, it represents an important candidate target for the development of new herbicides. To perform pharmacophore screening or shape similarity screening, a database with a larger diversity of small molecules should be selected. For this purpose, we chose ZINC free database which contains fragment libraries, drug pools, drug libraries, natural product libraries, etc. The ZINC free database was screened by virtual screening using transketolase as the target to obtain the potential transketolase inhibitors, and two novel series of amide derivatives were designed and synthesized based on the structural leads, which could increase the structural diversity and discover more potent inhibitors of transketolase
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