Strategies of Virtual Screening in Medicinal Chemistry

Virtual screening represents an effective computational strategy to rise-up the chances of finding new bioactive compounds by accelerating the time needed to move from an initial intuition to market. Classically, the most pursued approaches rely on ligand- and structure-based studies, the former employed when structural data information about the target is missing while the latter employed when X-ray/NMR solved or homology models are instead available for the target. The authors will focus on the most advanced techniques applied in this area. In particular, they will survey the key concepts of virtual screening by discussing how to properly select chemical libraries, how to make database curation, how to applying and- and structure-based techniques, how to wisely use post-processing methods. Emphasis will be also given to the most meaningful databases used in VS protocols. For the ease of discussion several examples will be presented.

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Tubulin structure at intermediate resolution

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100140634 ◽

1995 ◽

Vol 53 ◽

pp. 852-853

Author(s):

K. H. Downing ◽

S. G. Wolf ◽

E. Nogales

Keyword(s):

High Resolution ◽

Structural Data ◽

Therapeutic Drug ◽

Zinc Ions ◽

Two Dimensional ◽

X Ray Diffraction ◽

X Ray ◽

Negative Stain ◽

Functional Mechanisms ◽

Tubulin Structure

Microtubules are involved in a host of critical cell activities, many of which involve transport of organelles through the cell. Different sets of microtubules appear to form during the cell cycle for different functions. Knowledge of the structure of tubulin will be necessary in order to understand the various functional mechanisms of microtubule assemble, disassembly, and interaction with other molecules, but tubulin has so far resisted crystallization for x-ray diffraction studies. Fortuitously, in the presence of zinc ions, tubulin also forms two-dimensional, crystalline sheets that are ideally suited for study by electron microscopy. We have refined procedures for forming the sheets and preparing them for EM, and have been able to obtain high-resolution structural data that sheds light on the formation and stabilization of microtubules, and even the interaction with a therapeutic drug.Tubulin sheets had been extensively studied in negative stain, demonstrating that the same protofilament structure was formed in the sheets and microtubules. For high resolution studies, we have found that the sheets embedded in either glucose or tannin diffract to around 3 Å.

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Unraveling the action mechanism of Buyang Huanwu Tang (BYHWT) for Cerebral Ischemia by Systematic Pharmacological Methodology

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200901100529 ◽

2020 ◽

Vol 23 ◽

Author(s):

Shi-tang Ma ◽

Ning Zhang ◽

Ge Hong ◽

Cheng-tao Feng ◽

Sheng-wei Hong ◽

...

Keyword(s):

Cerebral Ischemia ◽

Virtual Screening ◽

Signaling Pathways ◽

Bioactive Compounds ◽

Enrichment Analysis ◽

Material Base ◽

Lead Discovery ◽

Binding Effect ◽

Bioactive Ingredients ◽

Compound Target

Background: Buyang Huanwu Tang (BYHWT) and relevant Traditional Chinese medicine (TCM) has its unique advantages in the treatment of cerebral ischemia. However, its pharmacological mechanism have not been fully explained. Objective: Base on the multi-component, also the entire disease network targets, the present study set out to identify major bioactive ingredients, key disease targets, and pathways of BYHWT against cerebral ischemia disease by systematic pharmacological methodology. Methods: Both the bioactive compounds from the BYHWT and the positive drugs against cerebral ischemia were fully investigated. The binding targets of the positive drugs were then obtained. A virtual screening protocol was then used to highlight the compound-target interaction. And network was constructed to visual the compound-target binding effect after docking analysis. Moreover，the targets enrichment analysis for biological processes and pathways were revealed to further explore the function of bio-targets protein gene and its role in the signal pathway. Results: A total of 382 active ingredients of the BYHWT and 23 candidate disease targets were identified. Virtual screening results indicated that multiple bioactive compounds targeted multiple proteins. Each compounds act on one or more targets. The mechanisms were linked to 20 signaling pathways, and the key mechanism was related to serotonergic synapse, calcium signaling pathway and camp signaling pathways. Conclusion: The present study explored the bioactive ingredients and mechanisms of BYHWT against cerebral ischemia by systematic pharmacological methodology. the novel methodology would provide a reference for the lead discovery of precursors, disease mechanism and material base for TCM.

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Plasma Fabrication and SERS Functionality of Gold Crowned Silicon Submicrometer Pillars

Materials ◽

10.3390/ma13051244 ◽

2020 ◽

Vol 13 (5) ◽

pp. 1244 ◽

Cited By ~ 1

Author(s):

Paola Pellacani ◽

Carlo Morasso ◽

Silvia Picciolini ◽

Dario Gallach ◽

Lucia Fornasari ◽

...

Keyword(s):

Raman Spectroscopy ◽

Surface Enhanced Raman Spectroscopy ◽

Post Processing ◽

Advanced Material ◽

X Ray ◽

Colloidal Monolayer ◽

Surface Enhanced ◽

Surface Enhanced Raman ◽

Lift Off ◽

X Ray Absorption

Sequential plasma processes combined with specific lithographic methods allow for the fabrication of advanced material structures. In the present work, we used self-assembled colloidal monolayers as lithographic structures for the conformation of ordered Si submicrometer pillars by reactive ion etching. We explored different discharge conditions to optimize the Si pillar geometry. Selected structures were further decorated with gold by conventional sputtering, prior to colloidal monolayer lift-off. The resulting structures consist of a gold crown, that is, a cylindrical coating on the edge of the Si pillar and a cavity on top. We analysed the Au structures in terms of electronic properties by using X-ray absorption spectroscopy (XAS) prior to and after post-processing with thermal annealing at 300 °C and/or interaction with a gold etchant solution (KI). The angular dependent analysis of the plasmonic properties was studied with Fourier transformed UV-vis measurements. Certain conditions were selected to perform a surface enhanced Raman spectroscopy (SERS) evaluation of these platforms with two model dyes, prior to confirming the potential interest for a well-resolved analysis of filtered blood plasma.

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Compressibility of β-As4S4: an in situ high-pressure single-crystal X-ray study

Mineralogical Magazine ◽

10.1180/minmag.2012.076.4.12 ◽

2012 ◽

Vol 76 (4) ◽

pp. 963-973 ◽

Cited By ~ 6

Author(s):

G. O. Lepore ◽

T. Boffa Ballaran ◽

F. Nestola ◽

L. Bindi ◽

D. Pasqual ◽

...

Keyword(s):

Pressure Range ◽

Substantial Reduction ◽

Structural Data ◽

Unit Cell ◽

Van Der Waals Interactions ◽

X Ray Diffraction ◽

Unit Cell Parameters ◽

X Ray ◽

Cell Parameters ◽

Intermolecular Distances

AbstractAmbient temperature X-ray diffraction data were collected at different pressures from two crystals of β-As4S4, which were made by heating realgar under vacuum at 295ºC for 24 h. These data were used to calculate the unit-cell parameters at pressures up to 6.86 GPa. Above 2.86 GPa, it was only possible to make an approximate measurement of the unit-cell parameters. As expected for a crystal structure that contains molecular units held together by weak van der Waals interactions, β-As4S4 has an exceptionally high compressibility. The compressibility data were fitted to a third-order Birch–Murnaghan equation of state with a resulting volume V0 = 808.2(2) Å3, bulk modulus K0 = 10.9(2) GPa and K' = 8.9(3). These values are extremely close to those reported for the low-temperature polymorph of As4S4, realgar, which contains the same As4S4 cage-molecule. Structural analysis showed that the unit-cell contraction is due mainly to the reduction in intermolecular distances, which causes a substantial reduction in the unit-cell volume (∼21% at 6.86 GPa). The cage-like As4S4 molecules are only slightly affected. No phase transitions occur in the pressure range investigated.Micro-Raman spectra, collected across the entire pressure range, show that the peaks associated with As–As stretching have the greatest pressure dependence; the S–As–S bending frequency and the As–S stretching have a much weaker dependence or no variation at all as the pressure increases; this is in excellent agreement with the structural data.

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Steric Parameters of Conformationally Flexible Ligands from X-ray Structural Data. 1. P(OR)3Ligands in Equivalent Ligand Environments

Organometallics ◽

10.1021/om000347a ◽

2000 ◽

Vol 19 (25) ◽

pp. 5273-5280 ◽

Cited By ~ 17

Author(s):

Jeremy M. Smith ◽

Neil J. Coville ◽

Leanne M. Cook ◽

Jan C. A. Boeyens

Keyword(s):

Structural Data ◽

X Ray ◽

Equivalent Ligand ◽

Flexible Ligands

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Purification, crystallization and preliminary X-ray diffraction analysis of a hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase (HCT) fromCoffea canephorainvolved in chlorogenic acid biosynthesis

Acta Crystallographica Section F Structural Biology and Crystallization Communications ◽

10.1107/s1744309112019082 ◽

2012 ◽

Vol 68 (7) ◽

pp. 824-828 ◽

Cited By ~ 3

Author(s):

Laura A. Lallemand ◽

James G. McCarthy ◽

Sean McSweeney ◽

Andrew A. McCarthy

Keyword(s):

Structural Data ◽

Coffea Canephora ◽

Molecular Replacement ◽

X Ray Diffraction ◽

X Ray ◽

Cell Parameters ◽

Key Enzyme ◽

Substrate Specifities ◽

Drop Technique ◽

Better Than

Chlorogenic acids (CGAs) are a group of soluble phenolic compounds that are produced by a variety of plants, includingCoffea canephora(robusta coffee). The last step in CGA biosynthesis is generally catalysed by a specific hydroxycinnamoyl-CoA quinate hydroxycinnamoyltransferase (HQT), but it can also be catalysed by the more widely distributed hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyltransferase (HCT). Here, the cloning and overexpression of HCT fromC. canephorainEscherichia colias well as its purification and crystallization are presented. Crystals were obtained by the sitting-drop technique at 293 K and X-ray diffraction data were collected on the microfocus beamline ID23-2 at the ESRF. The HCT crystals diffracted to better than 3.0 Å resolution, belonged to space groupP42212 with unit-cell parametersa=b= 116.1,c= 158.9 Å and contained two molecules in the asymmetric unit. The structure was solved by molecular replacement and is currently under refinement. Such structural data are needed to decipher the molecular basis of the substrate specifities of this key enzyme, which belongs to the large plant acyl-CoA-dependent BAHD acyltransferase superfamily.

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ChemInform Abstract: Evidence for the exo-Anomeric Stereoelectronic Effect in Cyclic Orthoester Aminals from X-Ray Structural Data. Crystal Structures of Three 2-Amino-1,3-oxazolidin-4-one Derivatives

ChemInform ◽

10.1002/chin.199111049 ◽

2010 ◽

Vol 22 (11) ◽

pp. no-no

Author(s):

V. BERTOLASI ◽

V. FERRETTI ◽

G. GILLI ◽

P. MARCHETTI ◽

F. D'ANGELI

Keyword(s):

Crystal Structures ◽

Structural Data ◽

X Ray ◽

Stereoelectronic Effect

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Virtual Screening and X-ray Crystallography Identify Non-Substrate Analog Inhibitors of Flavin-Dependent Thymidylate Synthase

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.6b00977 ◽

2016 ◽

Vol 59 (19) ◽

pp. 9269-9275 ◽

Cited By ~ 12

Author(s):

Rosaria Luciani ◽

Puneet Saxena ◽

Sachin Surade ◽

Matteo Santucci ◽

Alberto Venturelli ◽

...

Keyword(s):

Virtual Screening ◽

Thymidylate Synthase ◽

X Ray ◽

X Ray Crystallography ◽

Substrate Analog

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Textures Applied to Mechanical Processing Technology Assessment in Ancient Bronze

Materials Science Forum ◽

10.4028/www.scientific.net/msf.495-497.719 ◽

2005 ◽

Vol 495-497 ◽

pp. 719-724

Author(s):

R.E. Bolmaro ◽

B. Molinas ◽

E. Sentimenti ◽

A.L. Fourty

Keyword(s):

Orientation Distribution ◽

Distribution Functions ◽

Archaeological Sites ◽

Mechanical Processing ◽

Post Processing ◽

X Ray Diffraction ◽

Mechanical Process ◽

X Ray ◽

Pole Figures ◽

Microscopic Inspection

Some ancient metallic art craft, utensils, silverware and weapons are externally undistinguishable from modern ones. Not only the general aspect and shape but also some uses have not changed through the ages. Moreover, when just some small pieces can be recovered from archaeological sites, the samples can not easily be ascribed to any known use and consequently identified. It is clear that mechanical processing has changed along history but frequently only a "microscopic" inspection can distinguish among different techniques. Some bronze samples have been collected from the Quarto d’Altino (Veneto) archaeological area in Italy (paleovenetian culture) and some model samples have been prepared by a modern artisan. The sample textures have been measured by X-ray Diffraction techniques. (111), (200) and (220) pole figures were used to calculate Orientation Distribution Functions and further recalculate pole figures and inverse pole figures. The results were compared with modern forging technology results. Textures are able to discern between hammering ancient techniques for sheet production and modern industrial rolling procedures. However, as it is demonstrated in the present work, forgery becomes difficult to detect if the goldsmith, properly warned, proceeds to erase the texture history with some hammering post-processing. The results of this contribution can offer to the archaeologists the opportunity to take into consideration the texture techniques in order to discuss the origin (culture) of the pieces and the characteristic mechanical process developed by the ancient artisan. Texture can also help the experts when discussing the originality of a certain piece keeping however in mind the cautions indicated in this publication.

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