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Deganutti, Giuseppe (2016) Ligand-receptor recognition events decoded at molecular scale by means of molecular dynamics simulations. [Ph.D. thesis]

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Abstract (english)

During the last decades, the technological evolution has been very fast and has paved the way to a wide set of theoretical approaches able to support and stimulate the experimental component of biological sciences. From this standpoint, in drug discovery and design, the ability to make working hypothesis on how a small molecule interacts with its biological target can lead to rational approaches for the developing of new drug candidates.
Nowadays is possible to model the behaviour of chemical systems up to the atomistic scale, allowing retrieve insights on mechanisms behinds the ligand binding and unbinding from a receptor. Among the computational techniques available, molecular dynamics is able to take in account fundamental aspects linked to the time evolution of a biological system, such as structural flexibility and the dynamic role of water molecules in the protein binding sites.
During this Ph.D. project we employed molecular dynamics in order to disclose putative binding mechanisms of several ligands: more precisely, we applied the supervised molecular dynamics (SuMD) technique to decipher the binding pathways of both allosteric modulators and agonists to the adenosine receptors subtypes (belonging to class A of G protein-coupled receptors). Interestingly, findings highlights the coexistence of different potential recognition pathways that anticipate the formation of the orthosteric intermolecular complexes, as well as the crucial role of residues located at the extracellular portion of the protein.

Abstract (italian)

Nel corso degli ultimi decenni, l'evoluzione tecnologica è stata così rapida da aprire la strada a una vasta gamma di approcci teorici in grado di supportare e stimolare la componente sperimentale delle scienze biologiche. Da questo punto di vista, in drug design, la capacità di fornire ipotesi di lavoro su come una piccola molecola interagisce con il suo bersaglio biologico può portare ad approcci razionali per lo sviluppo di nuovi candidati farmaci.
Oggigiorno è possibile modellare il comportamento di sistemi chimici fino alla scala atomica, consentendo di avere informazioni sul meccanismo che guida associazione e dissociazione da un recettore. Tra le tecniche di calcolo disponibili, la dinamica molecolare è in grado di prendere in considerazione fondamentali aspetti legati all'€evoluzione temporale di un sistema biologico, quali la flessibilità strutturale e il ruolo dinamico delle molecole d'acqua nei siti di legame proteici.
Durante questo progetto di dottorato di ricerca abbiamo impiegato la dinamica molecolare al fine di rivelare i possibili meccanismi di riconoscimento di diversi ligandi, soprattutto nei confronti dei sottotipi recettoriali dell'adenosina (appartenenti alla classe A dei recettori accoppiati a proteine G): più precisamente, abbiamo applicato tecniche di dinamica molecolare supervisionata (SuMD) sia a modulatori allosterici che ad agonisti. E' interessante notare che i risultati evidenziano la co-esistenza di diversi possibili meccanismi di riconoscimento, che anticipano la formazione dei complessi intermolecolari ortosterici, oltre ad il ruolo cruciale di residui localizzati nella porzione proteica extracellulare.

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EPrint type:Ph.D. thesis
Tutor:Moro, Stefano
Ph.D. course:Ciclo 29 > Corsi 29 > SCIENZE MOLECOLARI
Data di deposito della tesi:27 December 2016
Anno di Pubblicazione:27 December 2016
Key Words:molecular binding molecular dynamics adenosine receptors
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:9810
Depositato il:17 Nov 2017 09:56
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