Binding Interactions of Ergotamine and Dihydroergotamine to 5-Hydroxytryptamine Receptor 1B (5-HT1b) Using Molecular Dynamics Simulations and Dynamic Network Analysis

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-HT1B). Although the high-resolution crystal structures of the 5-HT1B 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-HT1B 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-HT1B–ERG complex is in a more active conformation state than 5-HT1B–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 Trp3276.48 and Phe3316.52 as key residues involved in the active state 5-HT1B 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.