Leveraging X-Ray Structural Information in Gene Family-Based Drug Discovery

2007 ◽  
pp. 373-390
Author(s):  
Alex Aronov ◽  
Al Pierce ◽  
Guy Bemis ◽  
Marc Jacobs ◽  
Harmon Zuccola ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Gene Family ◽  
Structural Information ◽  
X Ray ◽  
Family Based

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.

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.

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.

Direct visualization of phase-separated domains in lipid membranes

1978 ◽  
Vol 36 (2) ◽  
pp. 290-291
Author(s):  
S. W. Hui ◽  
T. P. Stewart
Keyword(s):  
Lipid Membranes ◽  
Structural Information ◽  
Freeze Fracture ◽  
Biological Molecules ◽  
Vacuum Drying ◽  
Direct Visualization ◽  
X Ray Diffraction ◽  
Electron Microscopic ◽  
X Ray ◽  
Hydrocarbon Chains

Direct electron microscopic study of biological molecules has been hampered by such factors as radiation damage, lack of contrast and vacuum drying. In certain cases, however, the difficulties may be overcome by using redundent structural information from repeating units and by various specimen preservation methods. With bilayers of phospholipids in which both the solid and fluid phases co-exist, the ordering of the hydrocarbon chains may be utilized to form diffraction contrast images. Domains of different molecular packings may be recgnizable by placing properly chosen filters in the diffraction plane. These domains would correspond to those observed by freeze fracture, if certain distinctive undulating patterns are associated with certain molecular packing, as suggested by X-ray diffraction studies. By using an environmental stage, we were able to directly observe these domains in bilayers of mixed phospholipids at various temperatures at which their phases change from misible to inmissible states.

Characterizations of Synthetic 8mol% YSZ with Comparison to 3mol %YSZ for HT-SOFC

2020 ◽  
Vol 38 (4A) ◽  
pp. 491-500
Author(s):  
Abeer F. Al-Attar ◽  
Saad B. H. Farid ◽  
Fadhil A. Hashim
Keyword(s):  
Ionic Conductivity ◽  
Electrochemical Impedance ◽  
Structural Information ◽  
Impedance Analysis ◽  
High Energy ◽  
Yttria Stabilized Zirconia ◽  
X Ray Diffraction ◽  
Stabilized Zirconia ◽  
Powder Morphology ◽  
X Ray

In this work, Yttria (Y2O3) was successfully doped into tetragonal 3mol% yttria stabilized Zirconia (3YSZ) by high energy-mechanical milling to synthesize 8mol% yttria stabilized Zirconia (8YSZ) used as an electrolyte for high temperature solid oxide fuel cells (HT-SOFC). This work aims to evaluate the densification and ionic conductivity of the sintered electrolytes at 1650°C. The bulk density was measured according to ASTM C373-17. The powder morphology and the microstructure of the sintered electrolytes were analyzed via Field Emission Scanning Electron Microscopy (FESEM). The chemical analysis was obtained with Energy-dispersive X-ray spectroscopy (EDS). Also, X-ray diffraction (XRD) was used to obtain structural information of the starting materials and the sintered electrolytes. The ionic conductivity was obtained through electrochemical impedance spectroscopy (EIS) in the air as a function of temperatures at a frequency range of 100(mHz)-100(kHz). It is found that the 3YSZ has a higher density than the 8YSZ. The impedance analysis showed that the ionic conductivity of the prepared 8YSZ at 800°C is0.906 (S.cm) and it was 0.214(S.cm) of the 3YSZ. Besides, 8YSZ has a lower activation energy 0.774(eV) than that of the 3YSZ 0.901(eV). Thus, the prepared 8YSZ can be nominated as an electrolyte for the HT-SOFC.

Protein Interaction Domains and Post-Translational Modifications: Structural Features and Drug Discovery Applications

2020 ◽  
Vol 27 (37) ◽  
pp. 6306-6355 ◽  
Author(s):  
Marian Vincenzi ◽  
Flavia Anna Mercurio ◽  
Marilisa Leone
Keyword(s):  
Drug Discovery ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Structural Information ◽  
Protein Complexes ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
Modular Architecture ◽  
Post Translational Modifications ◽  
Interaction Domains

Background:: Many pathways regarding healthy cells and/or linked to diseases onset and progression depend on large assemblies including multi-protein complexes. Protein-protein interactions may occur through a vast array of modules known as protein interaction domains (PIDs). Objective:: This review concerns with PIDs recognizing post-translationally modified peptide sequences and intends to provide the scientific community with state of art knowledge on their 3D structures, binding topologies and potential applications in the drug discovery field. Method:: Several databases, such as the Pfam (Protein family), the SMART (Simple Modular Architecture Research Tool) and the PDB (Protein Data Bank), were searched to look for different domain families and gain structural information on protein complexes in which particular PIDs are involved. Recent literature on PIDs and related drug discovery campaigns was retrieved through Pubmed and analyzed. Results and Conclusion:: PIDs are rather versatile as concerning their binding preferences. Many of them recognize specifically only determined amino acid stretches with post-translational modifications, a few others are able to interact with several post-translationally modified sequences or with unmodified ones. Many PIDs can be linked to different diseases including cancer. The tremendous amount of available structural data led to the structure-based design of several molecules targeting protein-protein interactions mediated by PIDs, including peptides, peptidomimetics and small compounds. More studies are needed to fully role out, among different families, PIDs that can be considered reliable therapeutic targets, however, attacking PIDs rather than catalytic domains of a particular protein may represent a route to obtain selective inhibitors.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

Natural Sesquiterpene Lactones in the Prevention and Treatment of Inflammatory Disorders and cancer: A Systematic Study of this Emerging Therapeutic Approach based on Chemical and Pharmacological Aspect

2020 ◽  
Vol 17 (9) ◽  
pp. 1102-1116
Author(s):  
Sudip Kumar Mandal ◽  
Utsab Debnath ◽  
Amresh Kumar ◽  
Sabu Thomas ◽  
Subhash Chandra Mandal ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Biological Activities ◽  
Sesquiterpene Lactones ◽  
Structural Diversity ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Anti Cancer ◽  
Drug Discovery Program ◽  
Anti Inflammatory ◽  
Family Based

Background and Introduction: Sesquiterpene lactones are a class of secondary metabolite that contains sesquiterpenoids and lactone ring as pharmacophore moiety. A large group of bioactive secondary metabolites such as phytopharmaceuticals belong to this category. From the Asteraceae family-based medicinal plants, more than 5,000 sesquiterpene lactones have been reported so far. Sesquiterpene lactone-based pharmacophore moieties hold promise for broad-spectrum biological activities against cancer, inflammation, parasitic, bacterial, fungal, viral infection and other functional disorders. Moreover, these moiety based phytocompounds have been highlighted with a new dimension in the natural drug discovery program worldwide after the 2015 Medicine Nobel Prize achieved by the Artemisinin researchers. Objective: These bitter substances often contain an α, β-unsaturated-γ-lactone as a major structural backbone, which in recent studies has been explored to be associated with anti-tumor, cytotoxic, and anti-inflammatory action. Recently, the use of sesquiterpene lactones as phytomedicine has been increased. This study will review the prospect of sesquiterpene lactones against inflammation and cancer. Methods: Hence, we emphasized on the different features of this moiety by incorporating its structural diversity on biological activities to explore structure-activity relationships (SAR) against inflammation and cancer. Results: How the dual mode of action such as anti-inflammatory and anti-cancer has been exhibitedby these phytopharmaceuticals will be forecasted in this study. Furthermore, the correlation of anti-inflammatory and anti-cancer activity executed by the sesquiterpene lactones for fruitful phytotherapy will also be revealed in the present review in the milieu of pharmacophore activity relation and pharmacodynamics study as well. Conclusion: So, these metabolites are paramount in phytopharmacological aspects. The present discussion on the future prospect of this moiety based on the reported literature could be a guide for anti-inflammatory and anti-cancer drug discovery programs for the upcoming researchers.

scholarly journals Crystallization and preliminary X-ray analysis of thePlasmodium falciparumapicoplast DNA polymerase

2015 ◽  
Vol 71 (3) ◽  
pp. 333-337 ◽  
Author(s):  
Morgan E. Milton ◽  
Jun-yong Choe ◽  
Richard B. Honzatko ◽  
Scott W. Nelson
Keyword(s):  
Dna Polymerase ◽  
Structural Information ◽  
Klenow Fragment ◽  
X Ray Diffraction ◽  
Dna Polymerase I ◽  
X Ray ◽  
Cell Parameters ◽  
A Genome ◽  
Reported Data ◽  
Polymerase I

Infection by the parasitePlasmodium falciparumis the leading cause of malaria in humans. The parasite has a unique and essential plastid-like organelle called the apicoplast. The apicoplast contains a genome that undergoes replication and repair through the action of a replicative polymerase (apPOL). apPOL has no direct orthologs in mammalian polymerases and is therefore an attractive antimalarial drug target. No structural information exists for apPOL, and the Klenow fragment ofEscherichia coliDNA polymerase I, which is its closest structural homolog, shares only 28% sequence identity. Here, conditions for the crystallization of and preliminary X-ray diffraction data from crystals ofP. falciparumapPOL are reported. Data complete to 3.5 Å resolution were collected from a single crystal (2 × 2 × 5 µm) using a 5 µm beam. The space groupP6522 (unit-cell parametersa=b= 141.8,c= 149.7 Å, α = β = 90, γ = 120°) was confirmed by molecular replacement. Refinement is in progress.

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