Computational strategies to include protein flexibility in Ligand Docking and Virtual Screening

Buonfiglio, Rosa (2014) Computational strategies to include protein flexibility in Ligand Docking and Virtual Screening , [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Chimica, 26 Ciclo. DOI 10.6092/unibo/amsdottorato/6330.
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The dynamic character of proteins strongly influences biomolecular recognition mechanisms. With the development of the main models of ligand recognition (lock-and-key, induced fit, conformational selection theories), the role of protein plasticity has become increasingly relevant. In particular, major structural changes concerning large deviations of protein backbones, and slight movements such as side chain rotations are now carefully considered in drug discovery and development. It is of great interest to identify multiple protein conformations as preliminary step in a screening campaign. Protein flexibility has been widely investigated, in terms of both local and global motions, in two diverse biological systems. On one side, Replica Exchange Molecular Dynamics has been exploited as enhanced sampling method to collect multiple conformations of Lactate Dehydrogenase A (LDHA), an emerging anticancer target. The aim of this project was the development of an Ensemble-based Virtual Screening protocol, in order to find novel potent inhibitors. On the other side, a preliminary study concerning the local flexibility of Opioid Receptors has been carried out through ALiBERO approach, an iterative method based on Elastic Network-Normal Mode Analysis and Monte Carlo sampling. Comparison of the Virtual Screening performances by using single or multiple conformations confirmed that the inclusion of protein flexibility in screening protocols has a positive effect on the probability to early recognize novel or known active compounds.

Tipologia del documento
Tesi di dottorato
Buonfiglio, Rosa
Dottorato di ricerca
Scuola di dottorato
Scienze chimiche
Settore disciplinare
Settore concorsuale
Parole chiave
computational chemistry, ligand docking, virtual screening, protein flexibility, lactate dehydrogenase, opioid receptors, replica exchange molecular dynamics, monte carlo sampling, network analysis, cluster analysis
Data di discussione
14 Aprile 2014

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