Encoding mu-opioid receptor biased agonism with interaction fingerprints.

Opioids are potent painkillers, however, their therapeutic use requires close medical monitoring to diminish the risk of severe adverse effects. The G-protein biased agonists of the µ-opioid receptor (MOR) have shown safer therapeutic profiles than non-biased ligands. In this work, we performed extensive all-atom molecular dynamics simulations of two markedly biased ligands and a balanced reference molecule. From those simulations, we identified a protein-ligand interaction fingerprint that characterizes biased ligands. Then, we built and virtually screened a database containing 68,740 ligands with proven or potential GPCR agonistic activity. Exemplary molecules that fulfill the interacting pattern for biased agonism are showcased, illustrating the usefulness of this work for the search of biased MOR ligands and how this contributes to the understanding of MOR biased signaling.

Charge-transfer electronic states in organic solar cells: a TDDFT study.

The prediction of new organic photovoltaic materials in organic solar cells (OSCs) must include a precise description of charge-transfer states because they are involved in electron-transfer processes such as charge separation and charge recombination which govern the device efficiency. Also, as the experimental performance of an optoelectronic device is measured for nonequilibrium nanostructures, computational approaches need models that can incorporate morphology effects. Usually, this aspect is treated by molecular dynamics simulation (MDS) methodologies; however, methodologies and formalisms to calculate the electron-transfer processes are still controversial and sometimes do not connect their information with the phase morphologies. In this work we propose a simple and fast characterization of electron-transfer processes to find the rate constants by analysing the distribution of vertical excitation energies of both local excitation (LE) and charge-transfer (CT) states using TD-DFT calculations in the donor-acceptor pair structures which were extracted from MDS. This proposal assumes that conformational changes are prevented and equilibria are not achieved while the electron-transfer events take effect, and thus the only pathway that connects the LE and CT states is their surface crossing point where an ideal distribution might exist. Different density functionals and dialectric models were tested. The results indicate a close relationship between the proposal and experimental data for electron-transfer events, suggesting the application of this method in the rational design of new photovoltaic materials.

Atomistic simulations of bulk heterojunctions to evaluate the structural and packing properties of new predicted donors in OPVs.

Organic photovoltaic materials (OPVs), with low cost and structure flexibility, are of great interest and importance for their application in solar cell device development. However, the optimization of new OPV structures and the study of the structure arrangements and packing morphologies when materials are blended takes time and consumes raw materials, thus theoretical models could be of considerable value. In this work, we performed molecular dynamics simulations of present OPVs to understand the morphological packing of the donor-acceptor (DA) phases and DA heterojunction during evaporation and annealing processes, following inter and intramolecular properties like frontier orbitals, π-π stacking, coordination, distances, angles, and aggregation. Our considered donor molecules were selected from already proved experimental studies and also from predicted optimal compounds, designed through high throughput studies. The acceptor molecule employed in all our studied systems was PCBM ([6,6]-phenyl-C61-butyric acid methyl ester). Furthermore, we also analyze the influence of including different lateral aliphatic chains on the structural properties of the resulting DA packing morphologies. Our results can guide the design of new OPVs and subsequent studies applying charge transport and charge separation models.

Parameterization of prototype organic small molecules suitable for OPVs and molecular dynamics simulations: the BTT and BPT cases.

Organic photovoltaics (OPV) have been theoretically studied within the usual parameters: open circuit voltage (Voc), short circuit current (Jsc), and fill factor (FF). The first two refer mostly to electronic properties, whereas the last contains all other possible contributions to cell efficiency, importantly including molecular geometrical and topological structures, both within a single molecule as amongst a system of molecules. In order to study the effects of molecular morphology of the heterostructures used in OPVs, molecular dynamic simulations (MDS) are imperative, and therefore parameterization of force fields to account for the description of planarity between aromatic rings, both intra- and inter-molecules, is of key importance. In this work, we present quantum mechanical analysis of geometry for the ground, and singlet and triplet excited states, of two simple prototypical molecules used to parametrize the corresponding force-fields. Central for this parameterization is the assignment of local charges within molecules; we studied and compared six different methods to assign atomic charges. With the parameters obtained, we performed molecular dynamics simulations of nanosystems of these molecules. Planarity effects and comparison between different methods for deriving atomic charges are investigated. These results can be applied in future MDS to interpret and characterize charge-transfer models in molecules suitable for OPV design. Graphical Abstract Depiction of a replicated system of BTT and BPT molecules after simulation.

Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?

Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the µ opioid receptor (µ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few µ-OR agonists have been reported to selectively activate the Gi over ß-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression. Here, we discuss the strategies that led to the development of biased µ-OR agonists, and potential areas for improvement, with an emphasis on structural aspects of the ligand-receptor recognition process.