scholarly journals Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping

2019 ◽  
Vol 377 (2147) ◽  
pp. 20180422 ◽  
Author(s):  
Sherine E. Thomas ◽  
Patrick Collins ◽  
Rory Hennell James ◽  
Vitor Mendes ◽  
Sitthivut Charoensutthivarakul ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Three Dimensional ◽  
Mycobacterium Abscessus ◽  
Crystal Structure Analysis ◽  
Binding Modes ◽  
X Ray ◽  
Fragment Screening ◽  
Difference Fourier

Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 10 40 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as ‘warm spots’ for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources. This article is part of the theme issue ‘Fifty years of synchrotron science: achievements and opportunities’.

Perspectives on Fragment-based Drug Discovery: A Strategy Applicable to Diverse Targets

2021 ◽  
Vol 21 ◽  
Author(s):  
Qingxin Li ◽  
Congbao Kang
Keyword(s):  
Clinical Trials ◽  
Drug Discovery ◽  
Nmr Spectroscopy ◽  
Binding Modes ◽  
X Ray ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
Hit Rate ◽  
Powerful Strategy ◽  
Fragment Based Drug Discovery

: Fragment-based drug discovery (FBDD) is a strategy to develop potent lead molecules and is frequently used in drug discovery projects of the pharmaceutical industry. This method starts from identifying a small-molecule fragment which usually binds weakly to the target and follows with a hit-to-lead step in which the fragment is grown into potent molecules that bind tightly to the target to affect its function. Quite a few drugs and compounds in clinical trials are developed using this approach, making FBDD a powerful strategy in drug discovery. FBDD can be applied to multiple targets and the hit rate in screening can be used in target druggability assessment. In this mini-review, we provide a summary for the development of FBDD. In addition to giving a brief summary of the methods used in fragment screening, we highlight some methods that are critical in the fragment growth. Biophysical methods and carefully chemical modification of the fragments are the key elements in FBDD. We show several strategies that can be utilized in FBDD. We emphasize that NMR spectroscopy such as 19F-NMR and 1H-15N-HSQC experiment and X-ray crystallography are important in FBDD due to their roles in fragment screening and understanding the binding modes of the fragment hits, which provides a strategy for fragment growth.

Protein-Ligand Docking Methodologies and Its Application in Drug Discovery

2016 ◽  
pp. 196-219
Author(s):  
Sanchaita Rajkhowa ◽  
Ramesh C. Deka
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Drug Design ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Stable Complex ◽  
Scoring Functions ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Modern Drug

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

scholarly journals Formation of Three-Dimensional Electronic Networks Using Axially Ligated Metal Phthalocyanines as Stable Neutral Radicals

Crystals ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 747
Author(s):  
Ryoya Sato ◽  
Masaki Matsuda
Keyword(s):  
Three Dimensional ◽  
Crystal Structure Analysis ◽  
Charge Carriers ◽  
Electronic Systems ◽  
Metal Phthalocyanine ◽  
Molecular Conductors ◽  
Metal Phthalocyanines ◽  
X Ray ◽  
Electronic Networks ◽  
Electrical Resistivities

Organic π-radical crystals are potential single-component molecular conductors, as they involve charge carriers. We fabricated new organic π-radical crystals using axially ligated metal phthalocyanine anions ([MIII(Pc)L2]−) as starting materials. Electrochemical oxidation of [MIII(Pc)L2]− afforded single crystals of organic π-radicals of the type MIII(Pc)Cl2·THF (M = Co or Fe, THF = tetrahydrofuran), where the π-conjugated macrocyclic phthalocyanine ligand is one-electron oxidized. The X-ray crystal structure analysis revealed that MIII(Pc)Cl2 formed three-dimensional networks with π-π overlaps. The electrical resistivities of CoIII(Pc)Cl2·THF and FeIII(Pc)Cl2·THF at room temperature along the a-axis were 6 × 102 and 6 × 103 Ω cm, respectively, and were almost isotropic, meaning that MIII(Pc)Cl2·THF had three-dimensional electronic systems.

scholarly journals Natural Products as Modulators of Sirtuins

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3287 ◽  
Author(s):  
Berin Karaman Mayack ◽  
Wolfgang Sippl ◽  
Fidele Ntie-Kang
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Histone Deacetylases ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Class Iii ◽  
Drug Candidates ◽  
Starting Point ◽  
Recent Developments ◽  
Potent Drug

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials.

A fourfold interpenetrating diamond-like three-dimensional zinc(II) coordination polymer: synthesis, crystal structure and physical properties

2019 ◽  
Vol 75 (5) ◽  
pp. 504-507 ◽  
Author(s):  
Hui-Ru Chen
Keyword(s):  
Crystal Structure ◽  
Room Temperature ◽  
Three Dimensional ◽  
Fluorescence Emission ◽  
Crystal Structure Analysis ◽  
The Novel ◽  
X Ray Diffraction ◽  
Metal Compounds ◽  
X Ray ◽  
Coordination Framework

Excellent fluorescence properties are exhibited by d 10 metal compounds. The novel three-dimensional ZnII coordination framework, poly[[{μ2-bis[4-(2-methyl-1H-imidazol-1-yl)phenyl] ether-κ2 N 3:N 3′}(μ2-furan-2,5-dicarboxylato-κ2 O 2:O 5)zinc(II)] 1.76-hydrate], {[Zn(C6H2O5)(C20H18N4O)]·1.76H2O} n , has been prepared and characterized using IR spectroscopy, elemental analysis and single-crystal X-ray diffraction. The crystal structure analysis revealed that the compound exhibits a novel fourfold interpenetrating diamond-like network. This polymer also displays a strong fluorescence emission in the solid state at room temperature.

The stereochemistry of B -diketo complexes with trim ethylplatinum iv II. The crystal structure of ethyl(trim ethylplatini-)- acetoacetate

1960 ◽  
Vol 254 (1277) ◽  
pp. 218-228 ◽  
Keyword(s):  
Crystal Structure ◽  
Three Dimensional ◽  
Carbonyl Oxygen ◽  
Crystal Structure Analysis ◽  
Methyl Groups ◽  
Methylene Carbon ◽  
X Ray ◽  
Methylene Carbon Atom ◽  
Critical Account ◽  
Active Methylene

A three-dimensional X-ray crystal structure analysis of the complex between trimethyl platinum and ethylacetoacetate, (CH 3 ) 3 Pt CH 3 . CO. CH. CO OC 2 H 5 , has shown that the molecule is dimeric. In a monoclinic unit cell (a = 8.83, b = 14.12, c = 9.30 Å, β = 95°, space group P2 1 / c ) there are two centrosymmetrical dimeric molecules in which each platinum atom is octahedrally co-ordinated by three methyl groups, in the cis configuration, by the two carbonyl oxygen atoms of one β -ketoester and by the central, or ‘active methylene’ carbon atom of the other β -ketoester in the dimer. The structure is thus essentially the same as that of trimethyl 4:6-dioxononyl platinum (part I) and the result shows that complex formation via a tridentate β -diketo system is preferred to co-ordination through an ester oxygen. A critical account is given of the criteria used to judge the correctness of the results.

Single Crystal X-Ray Structural Determination: A Powerful Technique for Natural Products Research and Drug Discovery

2012 ◽  
Vol 545 ◽  
pp. 3-15
Author(s):  
Hoong Kun Fun ◽  
Suchada Chantrapromma ◽  
Nawong Boonnak
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Single Crystal ◽  
Natural Product ◽  
Structure Determination ◽  
Three Dimensional ◽  
X Ray ◽  
Powerful Technique ◽  
Determination Of Absolute Configuration

Drug discovery from natural products resources have been extensively studied. The most important step in the discovery process is the identification of compounds with interesting biological activity. Single crystal X-ray structure determination is a powerful technique for natural products research and drug discovery in which the detailed three-dimensional structures that emerge can be co-related to the activities of these structures. This article shall present (i) co-crystal structures, (ii) determination of absolute configuration and (iii) the ability to distinguish between whether a natural product compound is a natural product or a natural product artifact. All these three properties are unique to the technique of single crystal X-ray structure determination.

scholarly journals Assay Establishment and Validation of a High-Throughput Screening Platform for Three-Dimensional Patient-Derived Colon Cancer Organoid Cultures

2016 ◽  
Vol 21 (9) ◽  
pp. 931-941 ◽  
Author(s):  
Karsten Boehnke ◽  
Philip W. Iversen ◽  
Dirk Schumacher ◽  
María José Lallena ◽  
Rubén Haro ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Single Cells ◽  
Three Dimensional ◽  
Compound Screening ◽  
Organoid Cultures ◽  
Screening Platform ◽  
Disease Specific

The application of patient-derived three-dimensional culture systems as disease-specific drug sensitivity models has enormous potential to connect compound screening and clinical trials. However, the implementation of complex cell-based assay systems in drug discovery requires reliable and robust screening platforms. Here we describe the establishment of an automated platform in 384-well format for three-dimensional organoid cultures derived from colon cancer patients. Single cells were embedded in an extracellular matrix by an automated workflow and subsequently self-organized into organoid structures within 4 days of culture before being exposed to compound treatment. We performed validation of assay robustness and reproducibility via plate uniformity and replicate-experiment studies. After assay optimization, the patient-derived organoid platform passed all relevant validation criteria. In addition, we introduced a streamlined plate uniformity study to evaluate patient-derived colon cancer samples from different donors. Our results demonstrate the feasibility of using patient-derived tumor samples for high-throughput assays and their integration as disease-specific models in drug discovery.

scholarly journals Cocktailed fragment screening by X-ray crystallography of the antibacterial target undecaprenyl pyrophosphate synthase from Acinetobacter baumannii

2020 ◽  
Vol 76 (1) ◽  
pp. 40-46
Author(s):  
James H. Thorpe ◽  
Ian D. Wall ◽  
Robert H. Sinnamon ◽  
Amy N. Taylor ◽  
Robert A. Stavenger
Keyword(s):  
Drug Discovery ◽  
Acinetobacter Baumannii ◽  
Structural Data ◽  
X Ray ◽  
Traditional Medicines ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
Binding Pockets ◽  
Antibacterial Target ◽  
Robustness Check

Direct soaking of protein crystals with small-molecule fragments grouped into complementary clusters is a useful technique when assessing the potential of a new crystal system to support structure-guided drug discovery. It provides a robustness check prior to any extensive crystal screening, a double check for assay binding cutoffs and structural data for binding pockets that may or may not be picked out in assay measurements. The structural output from this technique for three novel fragment molecules identified to bind to the antibacterial target Acinetobacter baumannii undecaprenyl pyrophosphate synthase are reported, and the different physicochemical requirements of a successful antibiotic are compared with traditional medicines.

scholarly journals Application of hepatocyte-like cells to enhance hepatic safety risk assessment in drug discovery

2018 ◽  
Vol 373 (1750) ◽  
pp. 20170228 ◽  
Author(s):  
Dominic P. Williams
Keyword(s):  
Risk Assessment ◽  
Drug Discovery ◽  
High Throughput Screening ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Genetic Characteristics ◽  
Short Period ◽  
Donor Variation ◽  
Discovery Pipeline

Hepatic stress and injury from drugs continues to be a major concern within the pharmaceutical industry, leading to preclinical and clinical attrition precautionary warnings and post-market withdrawal of drugs. There is a requirement for more predictive and mechanistically accurate models to aid risk assessment. Primary human hepatocytes, subject to isolation stress, cryopreservation, donor-to-donor variation and a relatively short period of functional capability in two-dimensional cultures, are not suitable for high-throughput screening procedures. There are two areas within the drug discovery pipeline that the generation of a stable, metabolically functional hepatocyte-like cell with unlimited supply would have major impact. First, in routine, cell health risk-assessment assays where hepatic cell lines are typically deployed. Second, at later stages of the drug discovery pipeline approaching candidate nomination where bespoke/investigational studies refining and understanding the risk to patients use patient-derived induced pluripotent stem cell (iPSC) hepatocytes retaining characteristics from the patient, e.g. HLA susceptibility alleles, iPSC hepatocytes with defined disease phenotypes or genetic characteristics that have the potential to make the hepatocyte more sensitive to a particular stress mechanism. Functionality of patient-centric hepatocyte-like cells is likely to be enhanced when coupled with emerging culture systems, such as three-dimensional spheroids or microphysiological systems. Ultimately, the aspiration to confidently use human-relevant in vitro models to predict human-specific hepatic toxicity depends on the integration of promising emerging technologies. This article is part of the theme issue ‘Designer human tissue: coming to a lab near you’.

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