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Broflanilide (1), discovered by Mitsui Chemicals Agro, Inc., has a unique chemical structure characterized as a meta-diamide and exhibits high activity against various pests, including Lepidopteran, Coleopteran, and Thysanopteran pests. Because broflanilide has a novel mode of action, the Insecticide Resistance Action Committee (IRAC) categorized it as a member of a new group: Group 30. The meta-diamide structure was generated via drastic structural modification of a lead compound, flubendiamide (2), and the subsequent structural optimization of meta-diamides on each of its three benzene rings led to the discovery of broflanilide. In the present study, the details of the generation of meta-diamides from the lead compound and the structural optimization of meta-diamides are described.

The recently developed λ-dynamics free-energy based simulation method was used to study the binding of 10 five-member ring heterocycle derivatives to an artificial cavity created by mutagenesis inside cytochrome c peroxidase. Application of λ-dynamics to this system gives a reasonable estimate of the binding affinity of the ligands. This methodology also provides a means to explore the binding orientations and conformations of the ligands inside the binding pocket much better than does conventional MD. This is due to the scaling of forces inherent in the λ-dynamics method, which lowers the barriers separating different binding modes and conformations. Examination of the λ-dynamics trajectory of the ligands revealed alternative binding orientations and conformations not detected by crystallography. Furthermore, a λ-dynamics simulation starting from random initial orientations, in which some ligands take significantly different orientations as compared with those from the X-ray structure, successfully samples the X-ray crystallographic orientations in all ligands. Ligand sampling by conventional MD starting from same initial structures remains trapped in the local minima from which they start. Such efficient sampling of ligand orientations and conformations is expected to diminish the limitation that an initial ligand structure must be close to its true bound orientation in order to yield a reasonable estimate of the binding free energy.

The λ-dynamics simulation method was used to study the binding of 10 five-member ring heterocycle derivatives to an artificial cavity created inside cytochrome C peroxidase by mutagenesis. Application of λ dynamics using a multiple topology approach resulted in trapping in local minima. To extend the method to these cases, a new restraining potential was devised and added to the extended Hamiltonian. Two approximations were introduced in order to estimate the binding free energy within small simulation times using this potential: (a) The entropy terms related to the restraining potential are assumed to cancel, due to the similarity of the ligands. (b) The restraining potential calculated from the coordinates of the environmental atoms during a λ-dynamics simulation is assumed to be equal to that of the average coordinates. Relatively short λ-dynamics simulations with this restraining potential successfully yielded reasonable estimates of the binding affinity of the ligands as compared with both experimental data and free energy perturbation calculations. Long time λ-dynamics simulations with a ten-ligand system revealed that better ligands tend to have small statistical errors, which is appropriate for screening out the plausible ligands from all candidates. Furthermore, short time λ-dynamics simulations with ten identical ligands demonstrated that sufficient precision was achieved for putative discovery of tight binding ligands or guests.