Ainoleena Turku

University of Helsinki
Supervisor: Henri Xhaard
Funding: other
Date: 2012-01-01

Theoretical analysis of OX1 and OX2 orexin receptors and their interaction with activating and inhibiting molecules

Orexin receptors OX1 and OX2 with activating peptides orexin A and orexin B form a mechanism, which is essential in controlling sleep and feeding patterns. Malfunctions in this system reduce the quality of life. For the present small molecule agonists, which activate orexin system, are not known. Instead about one hundred orexin receptor antagonists are known and one of them, almorexant, is in phase III clinical trial for the treatment of insomnia. There are several clinical applications for orexin receptor agonists, e.g. treatment of sleep disorders (narcolepsia), obesity and diabetes, as well as drug addiction and cancer.

The aim of this work is theoretically characterize OX1 and OX2 receptors, orexin A- and B- peptides and small molecules, which interact with orexin receptors using molecular modeling, molecular dynamics simulations, molecular docking and pharmacophore modeling. These techniques enable studying the receptors in atomic level, which is not possible with biophysical techniques, because these receptors exist embedded in cell membrane and are therefore hard to express, purify and crystallize. Information obtained with this research would help developing new potential drugs or chemicals used in academic research of orexin receptors.

Molecular modeling approaches help us to understand the chemical properties of the molecules that are essential in binding to OX1 and OX2 receptors (objective 1). Molecular modeling and molecular dynamic simulations provide snapshot images of the receptor in time, which provide an opportunity to study the activation mechanism of the receptors (objective 2). This enables making the pharmacophore models of the properties, which are important for receptor binding, activation and specificity (objective 3). These pharmacophore models as well as previous receptor models are used for virtual screening of molecular libraries, in order to choose the molecules, which most likely bind to the orexin receptors (objective 4).