Title:X-ray Crystallography and Computational Docking for the Detection and Development of Protein–Ligand Interactions
Volume: 20
Issue: 4
Author(s): N.M. Kershaw, G.S.A. Wright, R. Sharma, S.V. Antonyuk, R.W. Strange, N.G. Berry, P.M. O'Neill and S.S. Hasnain
Affiliation:
Keywords:
Amyotrophic lateral sclerosis, computational chemistry, fragment-based drug discovery, ligand docking, superoxide dismutase, X-ray crystallography, neurodegenerative disorder, gene encoding, superoxide dismutase (SOD1), fragment-
based drug discovery (FBDD)
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.