Counting on Fragment Based Drug Design Approach for Drug Discovery

2019 ◽  
Vol 18 (27) ◽  
pp. 2284-2293 ◽  
Author(s):  
Aanchal Kashyap ◽  
Pankaj Kumar Singh ◽  
Om Silakari
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Structural Information ◽  
Binding Mode ◽  
New Drugs ◽  
Design Approach ◽  
X Ray ◽  
X Ray Crystallography ◽  
Success Stories

Fragment based drug design (FBDD) is a structure guided ligand design approach used in the process of drug discovery. It involves identification of low molecular weight fragments as hits followed by determination of their binding mode using X-ray crystallography and/or NMR spectroscopy. X-ray protein crystallography is one of the most sensitive biophysical methods used for screening and is least prone to false positives. It also provides detailed structural information of the protein–fragment complex at the atomic level. The retrieved binding information facilitates the optimization of fragments into drug like molecules. These identified molecules bind efficiently with the target proteins and form high quality binding interactions. Fragment-based screening using X-ray crystallography is, therefore, an efficient method for identifying binding hotspots on proteins that can be further exploited by chemists and biologists for the discovery of new drugs. The recent advancements in FBDD technique are illustrated in this review along with recently published success stories of FBDD technique in drug discovery.

Fragment-based drug discovery and its application to challenging drug targets

2017 ◽  
Vol 61 (5) ◽  
pp. 475-484 ◽  
Author(s):  
Amanda J. Price ◽  
Steven Howard ◽  
Benjamin D. Cons
Keyword(s):  
Molecular Weight ◽  
Drug Discovery ◽  
Drug Targets ◽  
Structural Information ◽  
New Drugs ◽  
Low Molecular Weight ◽  
Related Factor ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Based Drug Discovery

Fragment-based drug discovery (FBDD) is a technique for identifying low molecular weight chemical starting points for drug discovery. Since its inception 20 years ago, FBDD has grown in popularity to the point where it is now an established technique in industry and academia. The approach involves the biophysical screening of proteins against collections of low molecular weight compounds (fragments). Although fragments bind to proteins with relatively low affinity, they form efficient, high quality binding interactions with the protein architecture as they have to overcome a significant entropy barrier to bind. Of the biophysical methods available for fragment screening, X-ray protein crystallography is one of the most sensitive and least prone to false positives. It also provides detailed structural information of the protein–fragment complex at the atomic level. Fragment-based screening using X-ray crystallography is therefore an efficient method for identifying binding hotspots on proteins, which can then be exploited by chemists and biologists for the discovery of new drugs. The use of FBDD is illustrated here with a recently published case study of a drug discovery programme targeting the challenging protein–protein interaction Kelch-like ECH-associated protein 1:nuclear factor erythroid 2-related factor 2.

scholarly journals Protein X-ray Crystallography and Drug Discovery

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1030 ◽  
Author(s):  
Laurent Maveyraud ◽  
Lionel Mourey
Keyword(s):  
Drug Discovery ◽  
Structural Information ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
X Ray ◽  
Drug Candidates ◽  
X Ray Crystallography ◽  
Compound Libraries ◽  
Fragment Library ◽  
Invaluable Tool

With the advent of structural biology in the drug discovery process, medicinal chemists gained the opportunity to use detailed structural information in order to progress screening hits into leads or drug candidates. X-ray crystallography has proven to be an invaluable tool in this respect, as it is able to provide exquisitely comprehensive structural information about the interaction of a ligand with a pharmacological target. As fragment-based drug discovery emerged in the recent years, X-ray crystallography has also become a powerful screening technology, able to provide structural information on complexes involving low-molecular weight compounds, despite weak binding affinities. Given the low numbers of compounds needed in a fragment library, compared to the hundreds of thousand usually present in drug-like compound libraries, it now becomes feasible to screen a whole fragment library using X-ray crystallography, providing a wealth of structural details that will fuel the fragment to drug process. Here, we review theoretical and practical aspects as well as the pros and cons of using X-ray crystallography in the drug discovery process.

From Penicillin to the Ribosome: Revolutions in the Determination and Use of Molecular Structure in Chemistry and Biology

2004 ◽  
Vol 57 (9) ◽  
pp. 829 ◽  
Author(s):  
Edward N. Baker
Keyword(s):  
Biological Sciences ◽  
Molecular Structure ◽  
Structural Genomics ◽  
Structure Determination ◽  
Biological Function ◽  
Structural Information ◽  
Structure Based Drug Design ◽  
X Ray ◽  
X Ray Crystallography

A revolution in structural analysis is in progress in the biological sciences that parallels a similar revolution that took place in chemistry 40–50 years ago. This has major implications for chemistry, offering exciting opportunities at the interface between chemistry and biology. The advances are driven by the value of structural information in biology, for understanding biological function, and for applications in structure-based drug design and structural genomics. Two directions are apparent: towards technically challenging biological structures and assemblies, typified by the potassium channel and the ribosome; and towards high-throughput structure determination of many, smaller, proteins, as in structural genomics. In this review, the advances in molecular biology and in structure determination by X-ray crystallography that make these developments possible are discussed, together with appropriate examples.

Case studies in automatic modelling of thrombin, alpha-lactalbumin and other proteins, and implications for drug design

1992 ◽  
Vol 99 (1-2) ◽  
pp. 123-136 ◽  
Author(s):  
E. Platt ◽  
B. Robson
Keyword(s):  
Drug Design ◽  
Enzyme Inhibitors ◽  
Dynamic Nature ◽  
Crystallographic Groups ◽  
X Ray ◽  
X Ray Crystallography ◽  
Starting Point ◽  
Long Timescales ◽  
Surface Loops

Synopsis:In order to investigate and demonstrate objective modelling of proteins as a basis for drug design, we have sought to model several proteins in particularly persuasive circumstances. This is either (a) by filing the results of the model with an independent institution prior to X-ray determination of their structure, or (b) by using wholly automatic, general and reproducible methods, or (c) most often by both. Results suggest the ability to predict the core of the protein to an accuracy of about 1 Å rms deviation between predicted and experimental all-atom coordinates, and of surface loops in the range 1-4 Å rms deviation. Although the upper end of the latter scale seems disturbing, it turns out that many of the surface loops show such large variations for the same protein as studied by different crystallographic groups, particularly when no common protein is used as a starting point for refinement in both cases. Recognising the dynamic nature of some loops on enzymes, and including in the calculation the ability to handle dynamics over long timescales, allows analysis and refinement of enzyme inhibitors as pharmaceuticals. Here we analyse these aspects, particularly by reference to X-ray crystallography data.

Synthesis of enantiopure 2-aryl-2-methoxypropionic acids and determination of their absolute configurations by X-ray crystallography

Chirality ◽  
2008 ◽  
Vol 20 (3-4) ◽  
pp. 251-264 ◽  
Author(s):  
Satoshi Sekiguchi ◽  
Junpei Naito ◽  
Hiromi Taji ◽  
Yusuke Kasai ◽  
Akinori Sugio ◽  
...  
Keyword(s):  
X Ray ◽  
X Ray Crystallography

scholarly journals Unraveling the long-pursued Au144 structure by x-ray crystallography

2018 ◽  
Vol 4 (10) ◽  
pp. eaat7259 ◽  
Author(s):  
Nan Yan ◽  
Nan Xia ◽  
Lingwen Liao ◽  
Min Zhu ◽  
Fengming Jin ◽  
...  
Keyword(s):  
Metal Nanoparticles ◽  
Weak Interactions ◽  
Gold Nanoclusters ◽  
Atomic Level ◽  
High Quality ◽  
X Ray ◽  
X Ray Crystallography ◽  
Quantum Size ◽  
First Time

The transition from nanocluster to nanocrystal is a central issue in nanoscience. The atomic structure determination of metal nanoparticles in the transition size range is challenging and particularly important in understanding the quantum size effect at the atomic level. On the basis of the rationale that the intra- and interparticle weak interactions play critical roles in growing high-quality single crystals of metal nanoparticles, we have reproducibly obtained ideal crystals of Au144(SR)60 and successfully solved its structure by x-ray crystallography (XRC); this structure was theoretically predicted a decade ago and has long been pursued experimentally but without success until now. Here, XRC reveals an interesting Au12 hollow icosahedron in thiolated gold nanoclusters for the first time. The Au–Au bond length, close to that of bulk gold, shows better thermal extensibility than the other Au–Au bond lengths in Au144(SR)60, providing an atomic-level perspective because metal generally shows better thermal extensibility than nonmetal materials. Thus, our work not only reveals the mysterious, long experimentally pursued structure of a transition-sized nanoparticle but also has important implications for the growth of high-quality, single-crystal nanoparticles, as well as for the understanding of the thermal extensibility of metals from the perspective of chemical bonding.

Examining the structure of the mature amyloid fibril

2002 ◽  
Vol 30 (4) ◽  
pp. 521-525 ◽  
Author(s):  
O. S. Makin ◽  
L. C. Serpell
Keyword(s):  
Self Assembly ◽  
Rational Design ◽  
Amyloid Fibrils ◽  
Structural Information ◽  
X Ray ◽  
X Ray Crystallography ◽  
Cryo Electron Microscopy ◽  
Fibre Diffraction ◽  
Complementary Techniques ◽  
Mature Fibril

The pathogenesis of the group of diseases known collectively as the amyloidoses is characterized by the deposition of insoluble amyloid fibrils. These are straight, unbranching structures about 70–120 å (1 å = 0.1 nm) in diameter and of indeterminate length formed by the self-assembly of a diverse group of normally soluble proteins. Knowledge of the structure of these fibrils is necessary for the understanding of their abnormal assembly and deposition, possibly leading to the rational design of therapeutic agents for their prevention or disaggregation. Structural elucidation is impeded by fibril insolubility and inability to crystallize, thus preventing the use of X-ray crystallography and solution NMR. CD, Fourier-transform infrared spectroscopy and light scattering have been used in the study of the mechanism of fibril formation. This review concentrates on the structural information about the final, mature fibril and in particular the complementary techniques of cryo-electron microscopy, solid-state NMR and X-ray fibre diffraction.

ChemInform Abstract: Synthesis of cis-1-((2-Hydroxymethyl)cyclopentyl)uracil and Determination of Its Conformation by X-Ray Crystallography and AM1 Theoretical Calculations.

ChemInform ◽  
2010 ◽  
Vol 27 (43) ◽  
pp. no-no
Author(s):  
L. SANTANA ◽  
M. TEIJEIRA ◽  
E. URIARTE ◽  
C. TERAN ◽  
U. CASELLATO ◽  
...  
Keyword(s):  
Theoretical Calculations ◽  
X Ray ◽  
X Ray Crystallography
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