The project I conducted during my Master Thesis involved the identification of new dual Sigma1-NMDA Receptors ligands, active against neurodegenerative diseases. This work was performed in the Medicinal Chemistry Laboratory group coordinated by Prof. Collina (Drug Sciences Department, University of Pavia) and in collaboration with the Computational Chemistry team headed by Prof. Liedl (Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck). Neurodegenerative syndromes are a group of diseases characterized by a progressive loss of cognitive and motor neuronal functions, with no possibility of improvement and little therapeutic possibilities. One aspect of the complexity of these pathologies relies on the multifactorial nature of the patho-aetiological mechanisms behind their arousal. A recent and innovative approach to address this kind of diseases is the so-called Multi Target (MT) strategy: the design of new compounds able to interact and modulate several targets involved in the outbreak of the same syndrome. During my Master Thesis I had the possibility to continue the work that the Med Chem Lab group carried out since many years regarding Sigma Receptors and multi target drugs. We have worked on the expansion of a previously designed compound library of MT ligands interacting with Sigma1 receptor (S1R) and N-methyl-D-aspartate receptor (NMDAR). From the visual inspection of the binding pocket of Amino-Terminal Domain (ATD) of NDMAR and of NMDAR known allosteric inhibitors, we slightly modified the aforementioned ligands to create a second compound library of twenty-four derivatives hypothetically able to bind to the receptor. The next phase was the synthesis and the physico-chemical characterization of both the libraries for future assays. Then, thanks to well established in silico, methods I was able to predict their ability to cross the Blood-Brain Barrier. Lastly, I had the possibility to spend four months at the University of Innsbruck where I performed in silico studies and calculations of the binding free energies of those compounds towards NDMAR.
La mia tesi di Laurea Magistrale in Chimica e Tecnologia Farmaceutiche ha avuto come obiettivo l’identificazione di nuovi modulatori duali per i recettori Sigma1 e N-methyl-D-aspartate, potenzialmente attivi contro patologie neurodegenerative. Nonostante si tratti di malattie ampiamente studiate, non hanno ancora una cura efficace e sono tuttora considerate “unmet medical needs”. La strategia “multi-target” è uno degli approcci adottati sia in ambito accademico sia industriale per identificare nuovi potenziali farmaci utili per il trattamento di patologie complesse e multifattoriali come quelle neurodegenerative. Questo approccio consiste nell’individuazione di molecole in grado di modulare due o più recettori e/o cascate cellulari disfunzionali coinvolte nell’insorgenza della patologia studiata. Il mio lavoro di tesi si è inserito in questo abito e fa parte di un progetto di ricerca più ampio. Il gruppo di ricerca di Medicinal Chemistry dell’Università di Pavia, coordinato dalla Prof.ssa Collina, col quale ho lavorato per la preparazione della tesi, ha infatti in atto una ricerca volta all’identificazione di nuovi modulatori del recettore Sigma1, in grado di modulare anche altri recettori appartenenti allo stesso pathway biochimico. A partire dai risultati precedentemente ottenuti dal gruppo di ricerca, sono stati disegnati nuovi modulatori, con l’obiettivo di aumentare l’affinità nei confronti del recettore NMDA, mantenendo l’affinità per Sigma1. Ho dapprima completato una libreria di composti che aveva fornito risultati interessanti. Successivamente ho sintetizzato, una seconda serie di composti, strutturalmente correlata alla precedente. Dei nuovi composti ho studiato in silico la capacità di attraversare la barriera emato-encefalica. Infine, grazie al programma Erasmus Traineeship, ho avuto la possibilità di lavorare con il Prof. Liedl dell’Università di Innsbruck con il quale è in atto da tempo una collaborazione. Ho valutato in silico l’affinità tra i composti disegnati e il recettore NMDA attraverso simulazioni di dinamica molecolare e calcolo delle energie libere di legame. I saggi di affinità sono attualmente in corso.
Progettazione, sintesi, caratterizzazione e studio in silico di ligandi duali Sigma1R e NMDAR, potenzialmente attivi come agenti neuroprotettivi.
POZZETTI, LUCA
2018/2019
Abstract
The project I conducted during my Master Thesis involved the identification of new dual Sigma1-NMDA Receptors ligands, active against neurodegenerative diseases. This work was performed in the Medicinal Chemistry Laboratory group coordinated by Prof. Collina (Drug Sciences Department, University of Pavia) and in collaboration with the Computational Chemistry team headed by Prof. Liedl (Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck). Neurodegenerative syndromes are a group of diseases characterized by a progressive loss of cognitive and motor neuronal functions, with no possibility of improvement and little therapeutic possibilities. One aspect of the complexity of these pathologies relies on the multifactorial nature of the patho-aetiological mechanisms behind their arousal. A recent and innovative approach to address this kind of diseases is the so-called Multi Target (MT) strategy: the design of new compounds able to interact and modulate several targets involved in the outbreak of the same syndrome. During my Master Thesis I had the possibility to continue the work that the Med Chem Lab group carried out since many years regarding Sigma Receptors and multi target drugs. We have worked on the expansion of a previously designed compound library of MT ligands interacting with Sigma1 receptor (S1R) and N-methyl-D-aspartate receptor (NMDAR). From the visual inspection of the binding pocket of Amino-Terminal Domain (ATD) of NDMAR and of NMDAR known allosteric inhibitors, we slightly modified the aforementioned ligands to create a second compound library of twenty-four derivatives hypothetically able to bind to the receptor. The next phase was the synthesis and the physico-chemical characterization of both the libraries for future assays. Then, thanks to well established in silico, methods I was able to predict their ability to cross the Blood-Brain Barrier. Lastly, I had the possibility to spend four months at the University of Innsbruck where I performed in silico studies and calculations of the binding free energies of those compounds towards NDMAR.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/21201