Flower Micelle of Amphiphilic Random Copolymers in Aqueous Media

The structure of the flower micelle formed by an amphiphilic random copolymer, sodium (2-acrylamido)-2-methylpropanesulfonate and N-dodecylmethacrylamide p(AMPS/C12), in 0.05 M aqueous NaCl was investigated by fully atomistic molecular dynamics simulation as well as by light scattering, and the results were compared with the flower micelle model of the minimum loop size, recently proposed by Kawata et al. [Macromolecules 2007, 40, 1174−1180]. After a sufficiently long simulation time, simulated p(AMPS/C12) chain with the degree of polymerization of 200 and C12 content of 50 mol % formed a unicore micelle, of which radius of gyration was much smaller than the AMPS homopolymer with the same degree of polymerization. The simulated micellar structure was analyzed in terms of density distribution functions for dodecyl groups, the main chain, and sulfonate groups as functions of the radial distance r from the center of mass of dodecyl groups. Only dodecyl groups exist at r ≲ 1.5 nm, and the main chain and sulfonate groups distribute in the range of r between 1.5 and 3.5 nm, but there were dodecyl groups coexisting with the main chain and sulfonate groups beyond r = 1.5 nm. All these structural features, as well as hydrodynamic radius data for p(AMPS/C12) with C12 contents higher than ca. 20 mol % obtained by light scattering, agreed with the predictions of the flower micelle model of the minimum loop size

A Practical Use of Ligand Efficiency Indices Out of the Fragment-Based Approach: Ligand Efficiency-Guided Lead Identification of Soluble Epoxide Hydrolase Inhibitors

Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency