MolMeDB: Molecules on Membranes Database.

Biological membranes act as barriers or reservoirs for many compounds within the human body. As such, they play an important role in pharmacokinetics and pharmacodynamics of drugs and other molecular species. Until now, most membrane/drug interactions have been inferred from simple partitioning between octanol and water phases. However, the observed variability in membrane composition and among compounds themselves stretches beyond such simplification as there are multiple drug-membrane interactions. Numerous experimental and theoretical approaches are used to determine the molecule-membrane interactions with variable accuracy, but there is no open resource for their critical comparison. For this reason, we have built Molecules on Membranes Database (MolMeDB), which gathers data about over 3600 compound-membrane interactions including partitioning, penetration and positioning. The data have been collected from scientific articles published in peer-reviewed journals and complemented by in-house calculations from high-throughput COSMOmic approach to set up a baseline for further comparison. The data in MolMeDB are fully searchable and browsable by means of name, SMILES, membrane, method or dataset and we offer the collected data openly for further reuse and we are open to further additions. MolMeDB can be a powerful tool that could help researchers better understand the role of membranes and to compare individual approaches used for the study of molecule/membrane interactions.

Investigation of New Orexin 2 Receptor Modulators Using In Silico and In Vitro Methods.

The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1⁻L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC50 of 2.2 µM, offering some promise mainly for the treatment of insomnia.