Unit:
Κατεύθυνση ΒιοπληροφορικήLibrary of the School of Science
Author:
Xanthopoulos Kleanthis
Supervisors info:
Δρ. Μαρία Ζερβού, Ερευνήτρια Β’, Εργαστήριο Μοριακής Ανάλυσης, Ινστιτούτο Φαρμακευτικής Χημείας και Βιοτεχνολογίας, Εθνικό Ίδρυμα Ερευνών (ΕΙΕ)
Δρ. Θεοδώρα Καλογεροπούλου, Ερευνήτρια Α’, Εργαστήριο Φαρμακευτικής Χημείας, Ινστιτούτο Φαρμακευτικής Χημείας και Βιοτεχνολογίας, Εθνικό Ίδρυμα Ερευνών (ΕΙΕ)
Κωνσταντίνος Βοργιάς, Καθηγητής , Τμήμα Βιολογίας, ΕΚΠΑ
Original Title:
Χρήση μεθόδων μοριακής μοντελοποίησης για την βελτιστοποίηση νέων συνθετικών νευροστεροειδών με αγωνιστική δράση στους υποδοχείς νευροτροφινών
Translated title:
Optimization of new synthetic neurosteroids with agonist action towards the neurotrophin receptors, with the use of moledular modelling
Summary:
The p75NTR receptor is a pan-neurotrophin receptor which is associated with diverse and opposite actions, promoting either the survival or apoptosis of nerve cells. It is activated by all neurotrophins, as well as their precursor forms, and its pleiotropic signaling is dependent upon its interaction with other functional proteins and the co-expression of other receptors, such as the members of the Tropomyosin receptor kinase family (Trks) or sortilin.
Neurotrophin NGF (Nerve Growth Factor) interacts specifically with the TrkA receptor as well as the pan-neurotrophin receptor p75NTR. NGF holds a central role in the development and maintenance of nerve cells, exerting beneficial effects in neurodegenerative diseases. Its polypeptide nature and its hyperalgesic effects though, prevent its usefulness as a therapeutic agent.
BNN27, a C17-spiroepoxy steroid derivative of the endogenous neurosteroid dehydroepiandrosterone (DHEA), is a lead compound with strong neuroprotective and antiapoptic activity. It interacts specifically with TrkA and p75NTR, with which NGF interacts as well, with IC50 1.86 and 3.9 nM respectively, mimicking some of the neuroprotective and pro-survival effects of NGF. BNN27 effectively rescues from apoptosis NGF-dependent sympathetic and sensory neurons, penetrates the BBB and doesn’t induce hyperalgesia. BioNMR assays (1H-STD NMR) revealed that BNN27 interacts with the extracellular domains (ECDs) of TrkA and p75NTR, which consist the binding domain of NGF, as well as with their complexes with NGF.
In the present thesis we applied a series of computational methods in order to:
a) Locate the hot spot(s) of the interaction between BNN27 and p75NTRΕCD alone as well as between BNN27 and p75NTRΕCD’s complexed form with NGF.
b) Investigate thoroughly the interactions of BNN27 with p75NTRΕCD alone as well as with the NGF:p75NTRΕCD complex, and study the stability of these interactions in the course of time.
Towards thess aims a series of long time Molecular Dynamics simulations were performed, that studied the interactions of an ensemble of BNN27 molecules with the monomer p75NTRΕCD, the asymmetric complex of p75NTRECD/NGF 1:2 and a p75NTRECD /proNGF 2:2 complex modified to model human NGF.
These studies revealed the fruitful interaction of BNN27 with p75NTRΕCD as well as with its complexed form with NGF. Interestingly, the potential hot spots lay in the p75NTR/NGF interfacial region and more importantly molecular dynamics simulations highlighted the spontaneous migration of BNN27 from the balk water towards the proteins’ interfacial region and the development of stable interactions with crucial and important amino acids. As such, the obtained results may further guide the design of optimized ligands acting as neurotrophin mimetics.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
Neurotrophins, DHEA, Alzheimer's, Drug Design, p75 neurotrophin receptor, molecular dynamics
