Dokument: Development of novel nAChR modulators
| Titel: | Development of novel nAChR modulators | |||||||
| Weiterer Titel: | Development of novel nAChR modulators | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=68146 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260212-084424-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Kaiser, Jesko Fabian [Autor] | |||||||
| Dateien: |
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| Beitragende: | Gohlke, Holger [Gutachter] Prof. Dr. Kassack, Matthias [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | Despite being banned by international treaties, several chemical attacks using organophosphorus compounds (OPCs) have been recorded over the last decades. By inhibiting the acetylcholinesterase, OPCs cause an increase of ACh concentrations in the synaptic gap, resulting in muscle weakness and respiratory paralysis after desensitization of nicotinic acetylcholine receptors (nAChRs). The current treatment of OPC poisonings is insufficient, with no treatment option targeting nAChRs directly. Recent progress in this area was made by the identification of MB327, a positive allosteric modulator (PAM) of nAChRs, able to resensitize the receptor. However, MB327 also acts as inhibitor of nAChRs at slightly higher concentrations, counteracting its therapeutic effect. Experimental data indicates that the therapeutically relevant effect is being transmitted via an allosteric binding site, but the precise binding site remained unknown, making structure- and ligand-based optimization of the compounds demanding. Within this thesis, I focused on proposing a binding site for these compounds as well as identifying more potent analogs of known binders and compounds featuring novel chemotypes acting as PAMs in nAChRs.
More precisely, in PUBLICATION I, I predicted a novel allosteric binding site for MB327, MB327-PAM-1, by using blind docking experiments in combination with molecular dynamics (MD) simulations and rigidity analysis. By performing free ligand diffusion MD simulations, I disentangled that MB327 may also bind to the orthosteric binding site, probably explaining the inhibitory effect of the ligand at higher concentrations. Based on this knowledge, more potent analogs of MB327 could be designed. Furthermore, in PUBLICATION II, I unraveled the potential binding mode of UNC0646, a recently described binder in MB327-PAM-1 with increased affinity compared to MB327. Based on the knowledge gathered in the first two publications, structure- and ligand-based drug design approaches became feasible. In PUBLICATION III, I performed a variety of virtual screening approaches to identify more affine substituents of the UNC0646 quinazoline moiety and to identify novel chemotypes acting as PAMs with a higher affinity compared to MB327, enriching the pool of lead structures. In PUBLICATION IV, Grid Inhomogeneous Solvation Theory computations helped revealing entropically unfavored water molecules within MB327-PAM 1. Substituting these water molecules with novel substituents at the MB327 bispyridinium core resulted in an MB327 analog with higher potency compared to MB327. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 12.02.2026 | |||||||
| Dateien geändert am: | 12.02.2026 | |||||||
| Promotionsantrag am: | 26.06.2024 | |||||||
| Datum der Promotion: | 08.01.2025 |
