<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics"^^ . "Neurotrophins (NTs) are growth factors that regulate key functions of the nervous system. This is achieved through binding to four cell surface receptors. The capacity of NTs to modulate different functions of the nervous system has made them appealing as therapeutics for neurodegenerative disorders. However, due to their large size, administration to patients requires invasive methodologies. As a result, small molecule NT mimetics that can bind to NT receptors have emerged as a solution. In this thesis, I have performed computer-aided drug design of novel small-molecule NT mimetics that act as NT receptor agonists. Specifically, I tested with molecular docking the potential binding sites of the lead steroidal compound BNN-27, which is a known TrkA agonist and computationally evaluated several BNN-27 derivatives with the goal to prioritize some of them for organic synthesis. I also performed virtual screening of 9200 compounds synthesized at University of Caen (UNICAEN), from which I identified several fragments that could be used as substituents of BNN-27. From those, eight fragments were determined as TrkA binders via STD-NMR. I performed a further optimization of the best-scoring fragment and proposed the six most promising compounds for organic synthesis. I also performed extensive mechanistic studies of BNN-27 analogues that were identified experimentally as TrkA and TrkB NT receptor agonists. I showed via Molecular Dynamics (MD) simulations that the compounds inserted readily in the membrane, which suggested that the molecules might bind to the transmembrane (TM)domain of the NT receptors. Consequently, I used docking and MD simulations to probe for small molecule binding in the TM domain of TrkA and compared with calculations done on TrkB. The simulations showed non-specific transient interactions between the compounds and the TM helices of both TrkA and TrkB, while the simulations that started with the compounds at the interface of the TM helices showed dissociation of the small molecules and diffusion in the membrane. This suggests that\r\nadditional experimental data would be needed to shed light into the NT mimetic mechanism. Additionally to the small-molecule modeling, I performed mechanistic studies of the p75 NT receptor. I performed simulations of the glycosylated extracellular (EC) domain of the p75 receptor, which showed the glycan shielding of the protein is minimal, and instead the glycans might interfere with the binding kinetics of the NTs to the p75 receptor, which is known to be different than for the rest of the NT receptors. Then, I studied the dimerization of the TM helices of p75 with coarse-grained MD simulations. A range of interhelical crossing angles was observed which probably corresponds to the scissors-like movement that is expected to happen upon receptor activation. Finally, I modeled for the first time the full-length homodimeric structure of the p75 receptor with its glycans present and a NT bound. I inserted the whole structure in a neuronal-like membrane and simulated it. The simulations showed that the EC domains of p75 approach and lie on the membrane, while the intracellular (IC) domains also come close and interact with the membrane. Interestingly, in some replica simulations the two death domains, which are initially in contact in a presumably inactive state, dissociate from each other, an event expected to occur upon p75 activation. This is accompanied by a shorter distance between the TM helix C-termini. Thus, in this thesis, a potential activation event of the p75 receptor is presented for the first time in atomic detail, with an allosteric signal propagated through the TM helices to the IC domains. The neuronal membrane also seems to be involved in the observed activation events. Overall, this thesis suggests some novel NT mimetics and reveals the dynamics of the p75 NT receptor in a membrane, which can guide future studies of these systems for the treatment of neurodegenerative disorders."^^ . "2025" . . . . . . . "Athanasios Alexandros"^^ . "Tsengenes"^^ . "Athanasios Alexandros Tsengenes"^^ . . . . . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics (PDF)"^^ . . . "Tsengenes_PhD_thesis_2025.pdf"^^ . . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Computer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #37413 \n\nComputer-Aided Drug Design of Small-Molecule Neurotrophin Mimetics\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .