No abstract

Ergotamine (ERG) and dihydroergotamine (DHE), common migraine drugs, have small structural differences but lead to clinically important distinctions in their pharmacological profiles. For example, DHE is less potent than ERG by about 10-fold at the 5-hydroxytrptamine receptor 1B (5-HT 1B ). Although the high-resolution crystal structures of the 5-HT 1B receptor with both ligands have been solved, the high similarity between these two complex structures does not sufficiently explain their activity differences and the activation mechanism of the receptor. Hence, an examination of the dynamic motion of both drugs with the receptor is required. In this study, we ran a total of 6.0 μs molecular dynamics simulations on each system. Our simulation data show the subtle variations between the two systems in terms of the ligand−receptor interactions and receptor secondary structures. More importantly, the ligand and protein root-mean-square fluctuations (RMSFs) for the two systems were distinct, with ERG having a trend of lower RMSF values, indicating it to be bound tighter to 5-HT 1B with less fluctuations. The molecular mechanism−general born surface area (MM−GBSA) binding energies illustrate this further, proving ERG has an overall stronger MM−GBSA binding energy. Analysis of several different microswitches has shown that the 5-HT 1B −ERG complex is in a more active conformation state than 5-HT 1B −DHE, which is further supported by the dynamic network model, with reference to mutagenesis data with the critical nodes and the first three low-energy modes from the normal mode analysis. We also identify Trp327 6.48 and Phe331 6.52 as key residues involved in the active state 5-HT 1B for both ligands. Using the detailed dynamic information from our analysis, we made predictions for possible modifications to DHE and ERG that yielded five derivatives that might have more favorable binding energies and reduced structural fluctuations.

No abstract

It is shown that the above transition can be repressed (metastably) by using in place of pure ammonium nitrate a solid solution of potassium nitrate in ammonium nitrate. With such a solid solution containing 8 to 10% potassium nitrate, the temperature of the transition III → IV is depressed to about −20 °C. Such solid solutions can be prepared either by fusing the components together or by crystallizing from a mixed aqueous solution.

The dopamine D2 receptor (D2R) is the primary target for antipsychotic drugs. Besides schizophrenia, this receptor is linked to dementia, Parkinson's disease, and depression. Recent studies have shown that β-arrestin biased agonists at this receptor treat schizophrenia with less side effects. Although the high resolution structure of this receptor exists, the mechanism of biased agonism at the receptor is unknown. In this study, dopamine, the endogenous unbiased G-protein agonist, MLS1547, a G-protein biased agonist, and UNC9975, a G-protein antagonist and a β-arrestin biased agonist, were docked to a homology model of the whole D2R including all flexible loops, and molecular dynamics simulations were conducted to study the potential mechanisms of biased agonism. Our thorough analysis on the protein-ligand interaction, secondary structure, tertiary structure, structure dynamics, and molecular switches of all three systems indicates that ligand binding to transmembrane 3 might be essential for G-protein recruitment, while ligand binding to transmembrane 6 might be essential for β-arrestin recruitment. Our analysis also suggests changes in both the secondary and the tertiary structures of TM5 and TM7, molecular switches and ICL3 flexibility are important in biased signaling. Communicated by Ramaswamy H. Sarma.