Structure-Based Discovery and Synthesis of Potential Transketolase Inhibitors

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.

Novel factors contributing to fungal pathogenicity at early stages of Setosphaeria turcica infection

“…Understanding the S. turcica germination process and appressorium development, as well as related biological events, could lead to improved disease control, as these processes are one of the earliest stages of fungal preparation for plant infection. Our laboratory has a long‐time interest in and focuses on the molecular control of S. turcica pathogenicity and fungicide development (Cao et al, 2020 ; Huo et al, 2018 ). Fieldwork observations suggest that inhibition of appressorium development is an efficient strategy against S. turcica ‐mediated maize foliar disease (Zeng et al, 2020 ).…”

Design and Synthesis of N-phenyl Phthalimides as Potent Protoporphyrinogen Oxidase Inhibitors

“…The herbicidal activities of the test compounds against B. campestris , A. retroflexus and D. sanguinalis were evaluated by the small cup method and foliar spray method at 200 mg/L, according the following procedure [33,34]. With respect to the small cup method, generally, the test compound (20 mg) was dissolved in N , N -dimethylformamide (DMF) (1 mL) and then diluted in water containing 0.1% Tween 80 to a final concentration of 200 mg/L.…”

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

“…Currently, several approaches are available in the search and development of drugs [ 90 , 91 , 92 , 93 ]. Planning based on structure and mechanism of action has proven to be an efficient and less expensive strategy for developing new drugs [ 94 ]. A critical study showed that the most common drug targets are enzymes, particularly oxidoreductases, transferases and lyases.…”

“…Virtual screening allows a search for several chemical libraries of small molecules and selects those that best interact with the specific target’s catalytic site [ 94 , 143 , 144 , 145 ]. The application of this technique is well accepted, mainly in the lead discovery phase [ 146 , 147 ].…”