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X-ray Crystallography and Computational Docking for the Detection and Development of Protein–Ligand Interactions

DOI: 10.2174/0929867311320040008 DOI Help

Authors: Neil Kershaw (Molecular Biophysics Group, University of Liverpool, U.K.) , G.s.a. Wright (Molecular Biophysics Group, University of Liverpool, U.K.) , R. Sharma (Molecular Biophysics Group, University of Liverpool, U.K.) , Svetlana Antonyuk (Molecular Biophysics Group, University of Liverpool, U.K.) , Richard Strange (Molecular Biophysics Group, University of Liverpool, U.K.) , N.g. Berry (Molecular Biophysics Group, University of Liverpool, U.K.) , P.m. O'neill (Molecular Biophysics Group, University of Liverpool, U.K.) , S.s. Hasnain (Molecular Biophysics Group, University of Liverpool, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Current Medicinal Chemistry , VOL 20 , PAGES 569 - 575

State: Published (Approved)
Published: January 2013
Diamond Proposal Number(s): 8663

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective dysfunction and death of the upper and lower motor neurons. Median survival rates are between 3 and 5 years after diagnosis. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of familial forms of ALS (fALS). Herein, we describe a fragment- based drug discovery (FBDD) approach for the investigation of small molecule binding sites in SOD1. X-ray crystallography has been used as the primary screening method and has been shown to directly detect protein-ligand interactions which cannot be unambiguously identified using other biophysical methods. The structural requirements for effective binding at Trp32 are detailed for a series of quinazoline-containing compounds. The investigation of an additional site that binds a range of catecholamines and the use of computational modelling to assist fragment evolution is discussed. This study also highlights the importance of ligand solubility for successful Xray crystallographic campaigns in lead compound design.

Journal Keywords: Amyotrophic lateral sclerosis, computational chemistry, fragment-based drug discovery, ligand docking, superoxide dismutase, X-ray crystallography, neurodegenerative disorder, gene encoding, superoxide dismutase (SD1), fragment- based drug discovery (FBDD

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography

Other Facilities: SOLEIL