Exploration versus Exploitation in Global Atomistic Structure Optimization.

The ability to navigate vast energy landscapes of molecules, clusters, and solids is a necessity for discovering novel compounds in computational chemistry and materials science. For high-dimensional systems, it is only computationally feasible to search a small portion of the landscape, and hence, the search strategy is of critical importance. Introducing Bayesian optimization concepts in an evolutionary algorithm framework, we quantify the concepts of exploration and exploitation in global minimum searches. The method allows us to control the balance between probing unknown regions of the landscape (exploration) and investigating further regions of the landscape known to have low-energy structures (exploitation). The search for global minima structures proves significantly faster with the optimal balance for three test systems (molecular compounds) and to a lesser extent also for a crystalline surface reconstruction. In addition, global search behaviors are analyzed to provide reasonable grounds for an optimal balance for different problems.

Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase.

Liraglutide is a novel once-daily human glucagon-like peptide (GLP)-1 analog in clinical use for the treatment of type 2 diabetes. To study metabolism and excretion of [(3)H]liraglutide, a single subcutaneous dose of 0.75 mg/14.2 MBq was given to healthy males. The recovered radioactivity in blood, urine, and feces was measured, and metabolites were profiled. In addition, [(3)H]liraglutide and [(3)H]GLP-1(7-37) were incubated in vitro with dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) to compare the metabolite profiles and characterize the degradation products of liraglutide. The exposure of radioactivity in plasma (area under the concentration-time curve from 2 to 24 h) was represented by liraglutide (≥89%) and two minor metabolites (totaling ≤11%). Similarly to GLP-1, liraglutide was cleaved in vitro by DPP-IV in the Ala8-Glu9 position of the N terminus and degraded by NEP into several metabolites. The chromatographic retention time of DPP-IV-truncated liraglutide correlated well with the primary human plasma metabolite [GLP-1(9-37)], and some of the NEP degradation products eluted very close to both plasma metabolites. Three minor metabolites totaling 6 and 5% of the administered radioactivity were excreted in urine and feces, respectively, but no liraglutide was detected. In conclusion, liraglutide is metabolized in vitro by DPP-IV and NEP in a manner similar to that of native GLP-1, although at a much slower rate. The metabolite profiles suggest that both DPP-IV and NEP are also involved in the in vivo degradation of liraglutide. The lack of intact liraglutide excreted in urine and feces and the low levels of metabolites in plasma indicate that liraglutide is completely degraded within the body.