Biorational design

Biorational approaches have proven useful in the development of classes of herbicides which inhibit essential metaboHc pathways common to all plants and thus are specific to plants and have low toxicity to mammalian species. Biorational herbicide development remains a high risk endeavor since promising high activities observed in the laboratory may be nullified by factors such as limitations in plant uptake and translocation, and the instabiHty or inactivity of biochemical en2yme inhibitors under the harsher environmental conditions in the field. Despite these recogni2ed drawbacks, biorational design of herbicides has shown sufficient potential to make the study of herbicide modes of action an important and growing research area. 

Methods by which to find a biologically active compound may be classified as (a) random selection/screening (b) directed synthesis (c) natural product models and (d) biorational design. Allelochemical research can be considered as a natural product model. Generally, natural pesticides such as allelochemicals can be the biological compound(s) itself or products or parts of plant tissues. 

The biorational design of analogous compounds must take into account the asymmetry of 2-hydroxy dodecanoic acid since C-2 is an asymmetric carbon with possible R and S enantiomers. That the stereochemistry appears to be... 

Application of molecular modeling techniques to the biorational design of selective and environmentally safe crop protection chemicals is addressed. Sulfonylurea herbicides are used as an example to illustrate the kinds of biological information that can be known with modern technologies. An example of selective inhibitor design using computer graphics is presented. 

In this chapter, I will address how molecular modeling tools can be applied to the biorational design of selective and... 

Each method has its own advantages and its own preferential uses Enzyme assays are ideal tools to screen for new chemical leads and quickly optimize them, necessarily in connection with conventional in vivo tests They also are useful in the biorational design of new compounds with a specific, preselected mode of action And finally they are useful in confirming modes of action ... 

Five standard approaches to the generation of new areas for agrochemical (and pharmaceutical) research are commonly cited random screening speculative nthesis imitative ("me-too") chemistry biorational design and finally the exploitation of natural products (7). Although this last approach has found much commercial success in the development of novel insecticides (for example the pyrethroids), there are still relatively few examples of herbicides and fungicides which have been discovered in this way. This account describes the development of a new class of fungicides derived from the strobilurin family of natural products and related compounds, all of which are derivatives of P-methoxyacrylic acid. 

Fully understanding the interactions between chemicals and target organism is also an essential aspect of this biorational design approach. It is now possible to produce sufficient enzyme by the application of molecular biology techniques. Current advanced technologies also allow us to do crystallization and subsequent X-ray analysis in a timely manner. This can lead to constiuction of a molecular... 

Although biorational design has enjoyed limited success to date, this approach is advancing fast and promising in terms of finding potential to create effective crop protection compounds with novel modes of action. An excellent example was designing PDHc inhibitors as herbicides [2]. Details can be found in the following sections. 

Although PDHc can be foimd in microorganisms [12-15], plants [16-18], and mammals [19-21], the three-dimensional form and homology of the mammal s PDHc are different from their counterparts found in microorganisms and plants. Because of that, an effective herbicide that targets on plant PDHc should have no effect on animal PDHc and be safe for animals, including humans by biorational design. 

We tried to find a plant PDHc inhibitor by biorational design. 

Several OP compounds have been demonstrated to be one of the most potent PDHc inhibitors. Arming with this newly found favorable selectivity in acely-Iphosphonate 1-1 we believe that further studies in this biorational design approach for finding powerful and selective inhibitors is possible. 

Our systematic optimization approach from a sound basic research idea to create field-test candidate herbicide provided valuable information on chemistry and biology of alkylphosphonates. Our research confirmed that plant PDHc El could be a new target for herbicide R/D. We hope that our biorational design in the synthesis of the alkylphosphonates as plant PDHc El inhibiters, paved the way for other biorational designs to find new pesticides with novel mode of action in the future. 

Clacyfos exhibited an obvious advantage over those acylphosphinates or acy-Iphosphonates in enzyme-selective inhibition, crop safely, and effectiveness. It seems to be the first compound which shows practical herbicidal activity as a plant PDHc inhibitor. These results proved the rationality and effectiveness of our study on the biorational design of plant PDHc El inhibitor. 

The pyruvate dehydrogenase complex (PDHc) is one of the most important oxidoreductases in organisms. It catalyzes the oxidative decarboxylation of pyruvate to form acetyl CoA, which is a pivotal process in cellular metabolism. Therefore, targeting on plant PDHc is an interesting approach liom the biorational design point of view. PDHc has been reported to be one of the target enzymes affected by some herbicidal compounds. Some acefylphosphinates and acefy-Iphosphonates, which were prepared as potential mechanism-based inhibitors for... 

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