Probing biased activation of mu-opioid receptor by the biased agonist PZM21 using all atom molecular dynamics simulation.

Morphine is a commonly used opioid drug to treat acute pain by binding to the mu-opioid receptor (MOR), but its effective analgesic efficacy via triggering of the heterotrimeric G protein pathway is accompanied by a series of adverse side effects via triggering of the β-arrestin pathway. Recently, PZM21, a recently developed MOR biased agonist, shows preferentially activating the G protein pathway over β-arrestin pathway. However, there is no high-resolution receptor structure in complex with PZM21 and its action mechanism remains elusive.

Binding Interactions of Ergotamine and Dihydroergotamine to 5-Hydroxytryptamine Receptor 1B (5-HT) 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-HT). Although the high-resolution crystal structures of the 5-HT 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.

Analysis of vismodegib resistance in D473G and W535L mutants of SMO receptor and design of novel drug derivatives using molecular dynamics simulations.

Aims: Vismodegib is an effective antagonist of smoothened receptors for treatment of locally advanced or metastatic basal cell carcinoma. However, it often suffers from drug resistance due to mutations. Two common mutants, D473G and W535L, were found to cause serious drug resistance.