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The development of superstimulating semiochemicals using computational chemistry - VC0411

This study will investigate ways of discovering novel vertebrate semiochemicals which will deliver a super-normal stimulus to the receiving animal, providing a basis for the future development of potent pest attractants or repellents. Computer-based molecular modelling and computational chemistry will be used to investigate the interaction between small biologically active ligands and carrier proteins in mouse urine (the major urinary proteins (MUP)). Mouse and rat MUP will be used as model systems because structures of these molecules and their pheromone ligands have already been elucidated. Molecular dynamic simulations which describe binding characteristics of pheromones to MUP will be developed, using calculations based on physical principles of bonding theory (molecular mechanics), prediction of electron behaviour (quantum mechanics) and laws of motion as applied to atoms (molecular dynamics). Simulations will be used to investigate the characteristics that make small molecules ideal ligands for binding to, and releasing from MUP, in order to suggest optimal pheromone structures. In-vitro binding studies of 2 candidate pheromones with MUP will be performed to establish a preliminary relationship between chemical properties and biological activity, allowing design of a congeneric series of putative “super-stimulating pheromones”. Samples of these putative super-stimulating pheromones will be tested, using in-vitro binding assays to validate and improve the model. A QSAR model to predict the pheromone structures with optimal potency will be derived using one or more of the following techniques: conventional linear regression modelling of a range of physicochemical properties calculated from computational chemistry algorithms; genetic algorithms or cluster analysis matching chemical properties and biological activity; and 3D QSAR using comparative molecular field analysis in which properties of the molecules as a whole (e.g. surface charge distribution) are mapped against biological activity to form a 3D lattice. It is anticipated that this study will suggest novel ways of manipulating the behaviour of mammalian pests in general, and ultimately allow development of safer and more humane approaches to managing pest problems.
Time-Scale and Cost
From: 1998

To: 2000

Cost: £101,250
Contractor / Funded Organisations
Central Science Laboratory
Fields of Study
Wildlife Management