Rational pesticide design is now more feasible than ever – but what targets and molecules to choose?

Modern computational approaches allow the design of pesticides that act on any molecular target, but the choice of a new molecular target or targets for discovery is critical to the success of the resulting small-molecule pesticides. This Perspective discusses what properties should be considered when choosing molecular targets and what molecular properties of the pesticide should be avoided in order to postpone the evolution of non-target-site resistance. Several criteria are discussed: (i) choose targets that cannot be circumvented; (ii) design pesticides to target more than one protein, either different molecular targets or protein-protein interactions, in order to preclude the evolution of target-site resistance; (iii) choose targets that are low in quantity; (iv) choose targets where the binding domain is dissimilar to that in mammals; (v) choose targets that result in toxic compound accumulation when inhibited; (vi) choose targets with sufficient similarity in groups of pests; and (vii) avoid chemical scaffolds that are easily degraded to delay metabolic resistance. It is important to ascertain in advance that incomplete inhibition of the target enzyme results in pest death. Using these criteria can lead to new pesticides that are more likely to have a long market life.