Structure-based Rational Design of Pesticides
Current pesticide discovery, sometimes referred to as rational design and development (RDD), is the inventive process of finding new chemicals based on the knowledge of a biological target. In contrast to traditional methods relying on trial-and-error testing of chemical substances on pests and matching the apparent effects, RDD begins with a hypothesis that modulation of a specific biological target may have pest control effect, which relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography, NMR spectroscopy, or homology modeling.So we also call it structure-based pesticide design (SBPD).
Potency is always the first key point that researchers have mainly considered, and various techniques have been developed and employed to optimize the noncovalent interactions between the protein and ligand, such as H-bond and π-π stacking interaction, with the aim to obtain a number of candidates with a nanomolar or even picomolar inhibition potency.Secondly, designing a pesticide with the appropriate selectivity is another continual challenge that researchers have to face in SBPD. In many cases this objective is attained through trial and error, but some rational approaches have also been developed to guide the tuning of selectivity. Hence, development of new methodologies for molecular design to improve potency and selectivity,including DFT-QSAR, Pharmacophore-linked Fragment Virtual Screening (PFVS),Conformational Flexibility Analysis (CFA), Pesticidal Fragment library, and et.al. are essential ingredients of our studies.
Apart from potency and selectivity,resistance is a new challenge pesticide design. A lot of pesticide discovered via SBPD usually encounter resistance very rapidly, which is an intractable problem. Target mutation is an important mechanism of resistance to pesticide. If resistance risk due to target mutationis used as an additional criterion for candidate selection, it is possible to delay the development of resistance of a new pesticide obtained by SBPD.Therefore, developing new methods for pesticide resistance prediction due to target mutation is also an interesting and important task. Computational mutation scanning (CMS) was developed to treat target mutation induced pesticide resistance.
It is important to stress that the discovery of pesticides must be based on well-understood molecular targets. The design of lead chemistry and target specificity should be considered along with the understanding of the environmental and toxicity potential at the earliest stage of molecular design.The molecular target-oriented innovation of green chemical pesticides is the ultimate goal of our research, which has just began a long and difficult journey.