scholarly journals Biological Activity Profiles of Multitarget Ligands from X-ray Structures

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 794
Author(s):  
Christian Feldmann ◽  
Jürgen Bajorath
Keyword(s):  
Large Scale ◽  
Pharmaceutical Research ◽  
Data Consistency ◽  
Exploratory Research ◽  
Activity Data ◽  
X Ray ◽  
X Ray Crystallography ◽  
Large Scale Analysis ◽  
Compound Promiscuity ◽  
Different Sources

In pharmaceutical research, compounds with multitarget activity receive increasing attention. Such promiscuous chemical entities are prime candidates for polypharmacology, but also prone to causing undesired side effects. In addition, understanding the molecular basis and magnitude of multitarget activity is a stimulating topic for exploratory research. Computationally, compound promiscuity can be estimated through large-scale analysis of activity data. To these ends, it is critically important to take data confidence criteria and data consistency across different sources into consideration. Especially the consistency aspect has thus far only been little investigated. Therefore, we have systematically determined activity annotations and profiles of known multitarget ligands (MTLs) on the basis of activity data from different sources. All MTLs used were confirmed by X-ray crystallography of complexes with multiple targets. One of the key questions underlying our analysis has been how MTLs act in biological screens. The results of our analysis revealed significant variations of MTL activity profiles originating from different data sources. Such variations must be carefully considered in promiscuity analysis. Our study raises awareness of these issues and provides guidance for large-scale activity data analysis.

scholarly journals The critical role of QM/MM X-ray refinement and accurate tautomer/protomer determination in structure-based drug design

2020 ◽  
Author(s):  
Oleg Y. Borbulevych ◽  
Roger I. Martin ◽  
Lance M. Westerhoff
Keyword(s):  
Drug Design ◽  
Critical Role ◽  
Pharmaceutical Research ◽  
Energy Functional ◽  
Structural Refinement ◽  
Structure Based Drug Design ◽  
X Ray ◽  
X Ray Crystallography ◽  
Refinement Method ◽  
The Impact

Abstract Conventional protein:ligand crystallographic refinement uses stereochemistry restraints coupled with a rudimentary energy functional to ensure the correct geometry of the model of the macromolecule—along with any bound ligand(s)—within the context of the experimental, X-ray density. These methods generally lack explicit terms for electrostatics, polarization, dispersion, hydrogen bonds, and other key interactions, and instead they use pre-determined parameters (e.g. bond lengths, angles, and torsions) to drive structural refinement. In order to address this deficiency and obtain a more complete and ultimately more accurate structure, we have developed an automated approach for macromolecular refinement based on a two layer, QM/MM (ONIOM) scheme as implemented within our DivCon Discovery Suite and "plugged in" to two mainstream crystallographic packages: PHENIX and BUSTER. This implementation is able to use one or more region layer(s), which is(are) characterized using linear-scaling, semi-empirical quantum mechanics, followed by a system layer which includes the balance of the model and which is described using a molecular mechanics functional. In this work, we applied our Phenix/DivCon refinement method—coupled with our XModeScore method for experimental tautomer/protomer state determination—to the characterization of structure sets relevant to structure-based drug design (SBDD). We then use these newly refined structures to show the impact of QM/MM X-ray refined structure on our understanding of function by exploring the influence of these improved structures on protein:ligand binding affinity prediction (and we likewise show how we use post-refinement scoring outliers to inform subsequent X-ray crystallographic efforts). Through this endeavor, we demonstrate a computational chemistry ↔ structural biology (X-ray crystallography) "feedback loop" which has utility in industrial and academic pharmaceutical research as well as other allied fields.

scholarly journals xMDFF: molecular dynamics flexible fitting of low-resolution X-ray structures

2014 ◽  
Vol 70 (9) ◽  
pp. 2344-2355 ◽  
Author(s):  
Ryan McGreevy ◽  
Abhishek Singharoy ◽  
Qufei Li ◽  
Jingfen Zhang ◽  
Dong Xu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Large Scale ◽  
Protein Structures ◽  
Data Bank ◽  
Real Space ◽  
Low Resolution ◽  
X Ray ◽  
X Ray Crystallography ◽  
Atomic Structures ◽  
Electron Density Map

X-ray crystallography remains the most dominant method for solving atomic structures. However, for relatively large systems, the availability of only medium-to-low-resolution diffraction data often limits the determination of all-atom details. A new molecular dynamics flexible fitting (MDFF)-based approach, xMDFF, for determining structures from such low-resolution crystallographic data is reported. xMDFF employs a real-space refinement scheme that flexibly fits atomic models into an iteratively updating electron-density map. It addresses significant large-scale deformations of the initial model to fit the low-resolution density, as tested with synthetic low-resolution maps of D-ribose-binding protein. xMDFF has been successfully applied to re-refine six low-resolution protein structures of varying sizes that had already been submitted to the Protein Data Bank. Finally,viasystematic refinement of a series of data from 3.6 to 7 Å resolution, xMDFF refinements together with electrophysiology experiments were used to validate the first all-atom structure of the voltage-sensing protein Ci-VSP.

scholarly journals Leveraging glycomics data in glycoprotein 3D structure validation with Privateer

2020 ◽  
Author(s):  
Haroldas Bagdonas ◽  
Daniel Ungar ◽  
Jon Agirre
Keyword(s):  
Structural Biology ◽  
Large Scale ◽  
3D Structure ◽  
Structure Validation ◽  
X Ray ◽  
X Ray Crystallography ◽  
Glycosidic Bonds ◽  
Cryo Electron Microscopy ◽  
Structure Solution ◽  
Solution Methods

The heterogeneity, mobility and complexity of glycans in glycoproteins have been, and currently remain, significant challenges in structural biology. Those aspects present unique problems to the two most prolific techniques: X-ray crystallography and cryo-electron microscopy. At the same time, advances in mass spectrometry have made it possible to get deeper insights on precisely the information that is most difficult to recover by structure solution methods: full-length glycan composition, including linkage details for the glycosidic bonds. These developments have given rise to glycomics. Thankfully, several large scale glycomics initiatives have stored results in publicly-available databases, some of which can be accessed through API interfaces. In the present work, we will describe how the Privateer carbohydrate structure validation software has been extended to harness results from glycomics projects, and its use to greatly improve the validation of 3D glycoprotein structures.

scholarly journals Cover art

2016 ◽  
Vol 85 (1) ◽  
Author(s):  
Rakesh Gudimella
Keyword(s):  
Large Scale ◽  
Molecular Model ◽  
Essential Medicines ◽  
Chemical Formula ◽  
X Ray Diffraction ◽  
X Ray ◽  
X Ray Crystallography ◽  
Chemical Structures ◽  
Diffraction Patterns ◽  
Cover Art

Cover art by Rakesh Gudimella. In 1964, Dorothy Hodgkin won the Nobel Prize for the discovery of the structure of penicillin using the emerging technique of x-ray crystallography. The original x-ray diffraction patterns and the subsequent molecular model she created is shown in the foreground. Although the chemical formula of penicillin was known, its structure was not, making it difficult to produce on a large scale. Her discovery set us on the path to understanding antibiotic mechanisms and opened the door for the synthesis of cephalosporins and other important medications. The background shows the chemical structures of several lifesaving and influential drugs on the WHO List of Essential Medicines.

scholarly journals Covering complete proteomes with X-ray structures: a current snapshot

2014 ◽  
Vol 70 (11) ◽  
pp. 2781-2793 ◽  
Author(s):  
Marcin J. Mizianty ◽  
Xiao Fan ◽  
Jing Yan ◽  
Eric Chalmers ◽  
Christopher Woloschuk ◽  
...  
Keyword(s):  
Homology Modeling ◽  
Structure Determination ◽  
Large Scale ◽  
Structural Model ◽  
Target Selection ◽  
Three Dimensional ◽  
X Ray ◽  
X Ray Crystallography ◽  
Knowledge Based ◽  
Wide Range

Structural genomics programs have developed and applied structure-determination pipelines to a wide range of protein targets, facilitating the visualization of macromolecular interactions and the understanding of their molecular and biochemical functions. The fundamental question of whether three-dimensional structures of all proteins and all functional annotations can be determined using X-ray crystallography is investigated. A first-of-its-kind large-scale analysis of crystallization propensity for all proteins encoded in 1953 fully sequenced genomes was performed. It is shown that current X-ray crystallographic knowhow combined with homology modeling can provide structures for 25% of modeling families (protein clusters for which structural models can be obtained through homology modeling), with at least one structural model produced for each Gene Ontology functional annotation. The coverage varies between superkingdoms, with 19% for eukaryotes, 35% for bacteria and 49% for archaea, and with those of viruses following the coverage values of their hosts. It is shown that the crystallization propensities of proteomes from the taxonomic superkingdoms are distinct. The use of knowledge-based target selection is shown to substantially increase the ability to produce X-ray structures. It is demonstrated that the human proteome has one of the highest attainable coverage values among eukaryotes, and GPCR membrane proteins suitable for X-ray structure determination were determined.

scholarly journals X-ray Structure-Based Chemoinformatic Analysis Identifies Promiscuous Ligands Binding to Proteins from Different Classes with Varying Shapes

2020 ◽  
Vol 21 (11) ◽  
pp. 3782 ◽  
Author(s):  
Christian Feldmann ◽  
Jürgen Bajorath
Keyword(s):  
Large Scale ◽  
Wide Spectrum ◽  
Basic Research ◽  
Molecular Properties ◽  
Binding Modes ◽  
Target Structure ◽  
Computational Investigation ◽  
Activity Data ◽  
X Ray ◽  
Protein Classes

(1) Background: Compounds with multitarget activity are of interest in basic research to explore molecular foundations of promiscuous binding and in drug discovery as agents eliciting polypharmacological effects. Our study has aimed to systematically identify compounds that form complexes with proteins from distinct classes and compare their bioactive conformations and molecular properties. (2) Methods: A large-scale computational investigation was carried out that combined the analysis of complex X-ray structures, ligand binding modes, compound activity data, and various molecular properties. (3) Results: A total of 515 ligands with multitarget activity were identified that included 70 organic compounds binding to proteins from different classes. These multiclass ligands (MCLs) were often flexible and surprisingly hydrophilic. Moreover, they displayed a wide spectrum of binding modes. In different target structure environments, binding shapes of MCLs were often similar, but also distinct. (4) Conclusions: Combined structural and activity data analysis identified compounds with activity against proteins with distinct structures and functions. MCLs were found to have greatly varying shape similarity when binding to different protein classes. Hence, there were no apparent canonical binding shapes indicating multitarget activity. Rather, conformational versatility characterized MCL binding.

A compact superconducting ring as a radiation source for X-ray crystallography

1998 ◽  
Vol 5 (3) ◽  
pp. 333-335 ◽  
Author(s):  
H. Iwasaki ◽  
N. Kurosawa ◽  
S. Masui ◽  
S. Fujita ◽  
T. Yurugi ◽  
...  
Keyword(s):  
Large Scale ◽  
Beam Current ◽  
Imaging Plate ◽  
Anomalous Scattering ◽  
Organic Crystals ◽  
X Ray ◽  
X Ray Crystallography ◽  
Superconducting Ring ◽  
Electron Orbit ◽  
Diffraction Patterns

A compact superconducting storage ring installed at Ritsumeikan University is operated at an electron-beam energy of 0.575 GeV and an initial beam current of 300 mA. The radius of the circular electron orbit is as small as 0.5 m, suggesting that the radiation emitted contains short-wavelength components. With an imaging plate as a detector, X-ray precession diffraction patterns were recorded for organic single crystals within a reasonable period of time using radiation of wavelength 0.155 nm (8 keV) to 0.248 nm (5 keV). The use of the radiation in the structural study of organic crystals containing 3d metal atoms using the phenomena of anomalous scattering is described. If appropriately planned, X-ray diffraction and/or scattering experiments can be made at the compact ring without recourse to a large-scale ring.

scholarly journals Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Marcelo V. Liberato ◽  
Rodrigo L. Silveira ◽  
Érica T. Prates ◽  
Evandro A. de Araujo ◽  
Vanessa O. A. Pellegrini ◽  
...  
Keyword(s):  
Large Scale ◽  
Catalytic Domain ◽  
Glycoside Hydrolases ◽  
Induced Fit ◽  
X Ray ◽  
X Ray Crystallography ◽  
Enzymatic Mechanism ◽  
X Ray Scattering ◽  
Large Amplitude Motions ◽  
Dynamics Simulations

Abstract Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

scholarly journals Structure of SARS-CoV-2 ORF8, a rapidly evolving coronavirus protein implicated in immune evasion

2020 ◽  
Author(s):  
Thomas G. Flower ◽  
Cosmo Z. Buffalo ◽  
Richard M. Hooy ◽  
Marc Allaire ◽  
Xuefeng Ren ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Evasion ◽  
Immune Suppression ◽  
Molecular Basis ◽  
Large Scale ◽  
Terminal Sequence ◽  
Specific Sequence ◽  
X Ray ◽  
X Ray Crystallography ◽  
Rapid Spread

AbstractThe molecular basis for the severity and rapid spread of the COVID-19 disease caused by SARS-CoV-2 is largely unknown. ORF8 is a rapidly evolving accessory protein that has been proposed to interfere with immune responses. The crystal structure of SARS-CoV-2 ORF8 was determined at 2.04 Å resolution by x-ray crystallography. The structure reveals a ~60 residue core similar to SARS-CoV ORF7a with the addition of two dimerization interfaces unique to SARS-CoV-2 ORF8. A covalent disulfide-linked dimer is formed through an N-terminal sequence specific to SARS-CoV-2, while a separate non-covalent interface is formed by another SARS-CoV-2-specific sequence, 73YIDI76. Together the presence of these interfaces shows how SARS-CoV-2 ORF8 can form unique large-scale assemblies not possible for SARS-CoV, potentially mediating unique immune suppression and evasion activities.

Sign in / Sign up

Export Citation Format

Share Document