The nicotinic acetylcholine receptor (nAChR) plays a crucial role in the central nervous system of insects, and thus this target has become a major insecticidal mode of action. Synthetic agonist classes are superior to naturally occurring insecticides both in terms of mammalian safety as well as insecticidal control. Nevertheless, there is still room for innovation as exemplified by the identification of the butenolide insecticide SivantoTM (flupyradifurone). One of the approaches to its discovery was inspired by the stemofoline lactone �head group� and features of other nAChR agonists. As high resolution X-ray structures of the nAChR itself are, as of today, unavailable, rational design approaches based on protein structure are still limited. This situation was improved in recent years by crystallographic studies on acetylcholine binding proteins (AChBPs) and their co-crystals with various nAChR-agonists, as the overall architechture of AChBPs resembles the extracellular domains of nAChRs very well. However, even before the high resolution co-crystal structures paved the path towards better understanding of binding modes of nAChR-agonists, ligand based approaches to rational design were surprisingly successful. It is well known that electrostatics is a main driver of molecular recognition processes. In particular for agonists of nAChR, electrostatics has been identified very early on as a driving factor, well-suited for developing qualitative understanding as well as for QSAR purposes. Molecular interactions and molecular reactivity can be described in terms of Fukui functions. It has been shown that these functions can not only be used to rationalize metabolic behaviour but may also serve as molecular descriptors for agonistic activity. In this contribution, a simplistic chemometrics view on the novelty of the butenolide class, results from homology models and docking studies as well as quantum chemical calculations of molecular properties and their impact on the discovery of flupyradifurone will be shown.

Novelty of butenolide insecticide Sivanto<sup>TM</sup>: A computational chemistry perspective on its structure and bonding

248th National Meeting (2014)

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Novelty of butenolide insecticide SivantoTM: A computational chemistry perspective on its structure and bonding

Novelty of butenolide insecticide Sivanto^TM: A computational chemistry perspective on its structure and bonding