The Role of Crystallography in Drug Design

Deschamps, Jeffrey R.

doi:10.1007/978-0-387-76678-2_21

Cited by 8 publications

(2 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…X-ray crystallography is the primary method for determining the absolute configuration of a molecule and results from crystallographic studies provide unambiguous, accurate, and reliable 3-dimensional structural parameters, which are prerequisites for rational drug design and structure-based functional studies. Thus the role of crystallography in drug design is widely recognized (Cachau and Podjarny, 2005; Deschamps, 2005; Williams et al, 2005; Blundell et al, 2002; Wouters and Ooms, 2001). …”

Section: Introductionmentioning

confidence: 99%

X-ray crystallography of chemical compounds

Deschamps

2010

Life Sciences

Self Cite

View full text Add to dashboard Cite

Aims-Accurate knowledge of molecular structure is a prerequisite for rational drug design. This review examines the role of x-ray crystallography in providing the required structural information and advances in the field of x-ray crystallography that enhance or expand its role.Main Methods-X-ray crystallography of new drugs candidates and intermediates can provide valuable information of new syntheses and parameters for quantitative structure activity relationships (QSAR).Key Findings-Crystallographic studies play a vital role in many disciplines including materials science, chemistry, pharmacology, and molecular biology. X-ray crystallography is the most comprehensive technique available to determine molecular structure. A requirement for the high accuracy of crystallographic structures is that a 'good crystal' must be found, and this is often the rate-limiting step. In the past three decades developments in detectors, increases in computer power, and powerful graphics capabilities have contributed to a dramatic increase in the number of materials characterized by x-ray crystallography. More recently the advent of high-throughput crystallization techniques has enhanced our ability to produce that one good crystal required for crystallographic analysis.Significance-Continuing advances in all phases of a crystallographic study have expanded the ranges of samples which can be analyzes by x-ray crystallography to include larger molecules, smaller or weakly diffracting crystals, and twinned crystals.

show abstract

Section: Introductionmentioning

confidence: 99%

X-ray crystallography of chemical compounds

Deschamps

2010

Life Sciences

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although various biophysical methods exist, X-ray crystallography is considered the gold standard in fragment-based drug discovery (FBDD) as it can instantaneously provide detailed molecular information about the exact binding configuration of fragments [ 1 , 2 ]. This can then be exploited for subsequent rational structure-based drug design [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

High-Confidence Placement of Fragments into Electron Density Using Anomalous Diffraction—A Case Study Using Hits Targeting SARS-CoV-2 Non-Structural Protein 1

Mikhailik

Bowler

et al. 2023

IJMS

View full text Add to dashboard Cite

The identification of multiple simultaneous orientations of small molecule inhibitors binding to a protein target is a common challenge. It has recently been reported that the conformational heterogeneity of ligands is widely underreported in the Protein Data Bank, which is likely to impede optimal exploitation to improve affinity of these ligands. Significantly less is even known about multiple binding orientations for fragments (<300 Da), although this information would be essential for subsequent fragment optimisation using growing, linking or merging and rational structure-based design. Here, we use recently reported fragment hits for the SARS-CoV-2 non-structural protein 1 (nsp1) N-terminal domain to propose a general procedure for unambiguously identifying binding orientations of 2-dimensional fragments containing either sulphur or chloro substituents within the wavelength range of most tunable beamlines. By measuring datasets at two energies, using a tunable beamline operating in vacuum and optimised for data collection at very low X-ray energies, we show that the anomalous signal can be used to identify multiple orientations in small fragments containing sulphur and/or chloro substituents or to verify recently reported conformations. Although in this specific case we identified the positions of sulphur and chlorine in fragments bound to their protein target, we are confident that this work can be further expanded to additional atoms or ions which often occur in fragments. Finally, our improvements in the understanding of binding orientations will also serve to improve the rational optimisation of SARS-CoV-2 nsp1 fragment hits

show abstract