scholarly journals Common features of antibacterial compounds: an analysis of 10000 compounds library

2015 ◽  
Vol 61 (6) ◽  
pp. 785-790 ◽  
Author(s):  
M.S. Veselov ◽  
P.V. Sergiev ◽  
I.A. Osterman ◽  
D.A. Skvortsov ◽  
A.Ya. Golovina ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antibacterial Activity ◽  
Organic Compounds ◽  
High Throughput ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Molecular Target ◽  
Antibacterial Compounds ◽  
Common Features ◽  
Automated Screening

Antibacterial compounds are one of the essential classes of clinically important drugs. High throughput screening allowed revealing potential antibiotics active towards any molecular target in bacterial cell. We used a library of 9820 organic compounds with highly diversified structures to screen for antibacterial activity. As the result of automated screening, 103 compounds were found to possess antibacterial activity against Escherichia coli. The properties of these compounds were compared with those of initial library. Non-linear Kohonen mapping was used to analyze the differences between non-active molecules from initial library, identified antibacterial hits and compounds with reported antibacterial activity. It was found that identified antibacterial compounds are located in the separated area of chemical space. It can be therefore suggested that these molecules belong to novel classes of antibacterial compounds and could be studied further.

Large-scale High-throughput Screening Revealed 5'-(carbonylamino)-2,3'- bithiophene-4'-carboxylate as Novel Template for Antibacterial Agents

2020 ◽  
Vol 17 (5) ◽  
pp. 716-724
Author(s):  
Yan A. Ivanenkov ◽  
Renat S. Yamidanov ◽  
Ilya A. Osterman ◽  
Petr V. Sergiev ◽  
Vladimir A. Aladinskiy ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Large Scale ◽  
Antibacterial Agents ◽  
Sos Response ◽  
Luciferase Assay ◽  
Translational Machinery ◽  
E Coli ◽  
New Class

Background: The key issue in the development of novel antimicrobials is a rapid expansion of new bacterial strains resistant to current antibiotics. Indeed, World Health Organization has reported that bacteria commonly causing infections in hospitals and in the community, e.g. E. Coli, K. pneumoniae and S. aureus, have high resistance vs the last generations of cephalosporins, carbapenems and fluoroquinolones. During the past decades, only few successful efforts to develop and launch new antibacterial medications have been performed. This study aims to identify new class of antibacterial agents using novel high-throughput screening technique. Methods: We have designed library containing 125K compounds not similar in structure (Tanimoto coeff.< 0.7) to that published previously as antibiotics. The HTS platform based on double reporter system pDualrep2 was used to distinguish between molecules able to block translational machinery or induce SOS-response in a model E. coli system. MICs for most active chemicals in LB and M9 medium were determined using broth microdilution assay. Results: In an attempt to discover novel classes of antibacterials, we performed HTS of a large-scale small molecule library using our unique screening platform. This approach permitted us to quickly and robustly evaluate a lot of compounds as well as to determine the mechanism of action in the case of compounds being either translational machinery inhibitors or DNA-damaging agents/replication blockers. HTS has resulted in several new structural classes of molecules exhibiting an attractive antibacterial activity. Herein, we report as promising antibacterials. Two most active compounds from this series showed MIC value of 1.2 (5) and 1.8 μg/mL (6) and good selectivity index. Compound 6 caused RFP induction and low SOS response. In vitro luciferase assay has revealed that it is able to slightly inhibit protein biosynthesis. Compound 5 was tested on several archival strains and exhibited slight activity against gram-negative bacteria and outstanding activity against S. aureus. The key structural requirements for antibacterial potency were also explored. We found, that the unsubstituted carboxylic group is crucial for antibacterial activity as well as the presence of bulky hydrophobic substituents at phenyl fragment. Conclusion: The obtained results provide a solid background for further characterization of the 5'- (carbonylamino)-2,3'-bithiophene-4'-carboxylate derivatives discussed herein as new class of antibacterials and their optimization campaign.

Inhibition Profiling of Urease and Carbonic Anhydrase II by High- Throughput Screening and Molecular Docking Studies of Structurally Diverse Organic Compounds

2020 ◽  
Vol 17 ◽  
Author(s):  
Majid Ali ◽  
Syed Majid Bukhari ◽  
Asma Zaidi ◽  
Farhan A. Khan ◽  
Umer Rashid ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
Metal Complexes ◽  
Organic Compounds ◽  
High Throughput ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Carbonic Anhydrase Ii ◽  
Molecular Docking Studies ◽  
Ic50 Values

Background:: Structurally diverse organic compounds and available drugs were screened against urease and carbonic anhydrase II in a formulation acceptable for high-throughput screening. Objective: The study was conducted to find out potential inhibitors of urease and carbonic anhydrase II. Methods:: Quantification of the possible HITs was carried out by determining their IC50 values. Results and Discussion:: of several screened compounds including derivatives of oxadiazole, coumarins, chromane-2, 4- diones and metal complexes of cysteine-omeprazole showed promising inhibitory activities with IC50 ranging from 47 μM to 412 μM against the urease. The interactions of active compounds with active sites of enzymes were investigated through molecular docking studies which revealed that (R)-1-(4-amino-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl) butyl) guanidine possessing IC50 of 47 μM, interacts with one of the nickel metal atom of urease besides further interactions as predictable hydrogen bonds with KCX490, Asp633, His492, His407 and His409 along with Ala440 and 636. Bi-ligand metal complexes of 4-aminoantipyrine based Schiff bases showed activation of urease with AC50 ranging from 68 μM to 112 μM. Almost 21 compounds with varying functional groups including pyrimidines, oxadiazoles, imidazoles, hydrazides and tin based compounds were active carbonic anhydrase II inhibitors presenting 98 μM to 390 μM IC50 values. Several N-substituted sulfonamide derivatives were inactive against carbonic anhydrase II. Conclusion:: Among all the screened compounds, highly active inhibitor of carbonic anhydrase II was (4-(3- hydroxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl) methanone with IC50 of 98.0 μM. This particular compound showed metallic interaction with Zn ion of carbonic anhydrase II through hydroxyl group of phenyl ring.

scholarly journals A High-Throughput Approach To Identify Compounds That Impair Envelope Integrity in Escherichia coli

2016 ◽  
Vol 60 (10) ◽  
pp. 5995-6002 ◽  
Author(s):  
Kristin R. Baker ◽  
Bimal Jana ◽  
Henrik Franzyk ◽  
Luca Guardabassi
Keyword(s):  
Escherichia Coli ◽  
High Throughput ◽  
High Throughput Screening ◽  
Gram Negative Bacteria ◽  
Chromogenic Substrate ◽  
Intrinsic Resistance ◽  
Gram Negative ◽  
Content Type ◽  
E Coli ◽  
Screening Platform

ABSTRACTThe envelope of Gram-negative bacteria constitutes an impenetrable barrier to numerous classes of antimicrobials. This intrinsic resistance, coupled with acquired multidrug resistance, has drastically limited the treatment options against Gram-negative pathogens. The aim of the present study was to develop and validate an assay for identifying compounds that increase envelope permeability, thereby conferring antimicrobial susceptibility by weakening of the cell envelope barrier in Gram-negative bacteria. A high-throughput whole-cell screening platform was developed to measureEscherichia colienvelope permeability to a β-galactosidase chromogenic substrate. The signal produced by cytoplasmic β-galactosidase-dependent cleavage of the chromogenic substrate was used to determine the degree of envelope permeabilization. The assay was optimized by using known envelope-permeabilizing compounds andE. coligene deletion mutants with impaired envelope integrity. As a proof of concept, a compound library comprising 36 peptides and 45 peptidomimetics was screened, leading to identification of two peptides that substantially increased envelope permeability. Compound 79 reduced significantly (from 8- to 125-fold) the MICs of erythromycin, fusidic acid, novobiocin and rifampin and displayed synergy (fractional inhibitory concentration index, <0.2) with these antibiotics by checkerboard assays in two genetically distinctE. colistrains, including the high-risk multidrug-resistant, CTX-M-15-producing sequence type 131 clone. Notably, in the presence of 0.25 μM of this peptide, both strains were susceptible to rifampin according to the resistance breakpoints (R> 0.5 μg/ml) for Gram-positive bacterial pathogens. The high-throughput screening platform developed in this study can be applied to accelerate the discovery of antimicrobial helper drug candidates and targets that enhance the delivery of existing antibiotics by impairing envelope integrity in Gram-negative bacteria.

scholarly journals ChemSpaX: Exploration of Chemical Space by Automated Functionalization of Molecular Scaffold

2021 ◽  
Author(s):  
Adarsh Kalikadien ◽  
Evgeny A. Pidko ◽  
Vivek Sinha
Keyword(s):  
Force Field ◽  
High Throughput ◽  
High Throughput Screening ◽  
Chemical Space ◽  
Space Exploration ◽  
Molecular Structures ◽  
Data Driven ◽  
Pincer Complexes ◽  
Cobalt Porphyrin ◽  
Input Structure

<div>Local chemical space exploration of an experimentally synthesized material can be done by making slight structural</div><div>variations of the synthesized material. This generation of many molecular structures with reasonable quality,</div><div>that resemble an existing (chemical) purposeful material, is needed for high-throughput screening purposes in</div><div>material design. Large databases of geometry and chemical properties of transition metal complexes are not</div><div>readily available, although these complexes are widely used in homogeneous catalysis. A Python-based workflow,</div><div>ChemSpaX, that is aimed at automating local chemical space exploration for any type of molecule, is introduced.</div><div>The overall computational workflow of ChemSpaX is explained in more detail. ChemSpaX uses 3D information,</div><div>to place functional groups on an input structure. For example, the input structure can be a catalyst for which one</div><div>wants to use high-throughput screening to investigate if the catalytic activity can be improved. The newly placed</div><div>substituents are optimized using a computationally cheap force-field optimization method. After placement of</div><div>new substituents, higher level optimizations using xTB or DFT instead of force-field optimization are also possible</div><div>in the current workflow. In representative applications of ChemSpaX, it is shown that the structures generated by</div><div>ChemSpaX have a reasonable quality for usage in high-throughput screening applications. Representative applications</div><div>of ChemSpaX are shown by investigating various adducts on functionalized Mn-based pincer complexes,</div><div>hydrogenation of Ru-based pincer complexes, functionalization of cobalt porphyrin complexes and functionalization</div><div>of a bipyridyl functionalized cobalt-porphyrin trapped in a M2L4 type cage complex. Descriptors such as</div><div>the Gibbs free energy of reaction and HOMO-LUMO gap, that can be used in data-driven design and discovery</div><div>of catalysts, were selected and studied in more detail for the selected use cases. The relatively fast GFN2-xTB</div><div>method was used to calculate these descriptors and a comparison was done against DFT calculated descriptors.</div><div>ChemSpaX is open-source and aims to bolster the efforts of the scientific community towards data-driven material</div><div>discovery.</div>

scholarly journals Computational High-Throughput Screening of Polymeric Photocatalysts: Exploring the Effect of Composition, Sequence Isomerism and Conformational Degrees of Freedom

2018 ◽  
Author(s):  
isabelle Heath-Apostolopoulos ◽  
Liam Wilbraham ◽  
Martijn Zwijnenburg
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Degrees Of Freedom ◽  
Chemical Space ◽  
Low Cost ◽  
Computational Screening ◽  
Computational Workflow ◽  
Conformational Degrees Of Freedom

We discuss a low-cost computational workflow for the high-throughput screening of polymeric photocatalysts and demonstrate its utility by applying it to a number of challenging problems that would be difficult to tackle otherwise. Specifically we show how having access to a low-cost method allows one to screen a vast chemical space, as well as to probe the effects of conformational degrees of freedom and sequence isomerism. Finally, we discuss both the opportunities of computational screening in the search for polymer photocatalysts, as well as the biggest challenges.

scholarly journals Development of a Simple Assay Protocol for High-Throughput Screening of Mycobacterium tuberculosis Glutamine Synthetase for the Identification of Novel Inhibitors

2005 ◽  
Vol 10 (7) ◽  
pp. 725-729 ◽  
Author(s):  
Upasana Singh ◽  
Vinita Panchanadikar ◽  
Dhiman Sarkar
Keyword(s):  
Escherichia Coli ◽  
Mycobacterium Tuberculosis ◽  
Glutamine Synthetase ◽  
Small Molecules ◽  
High Throughput ◽  
High Throughput Screening ◽  
Coli Strain ◽  
Compound Library ◽  
Essential Enzyme ◽  
Assay Protocol

Mycobacterium tuberculosis glutamine synthetase (GS) is an essential enzyme involved in the pathogenicity of the organism. The screening of a compound library using a robust high-throughput screening (HTS) assay is currently thought to be the most efficient way of getting lead molecules, which are potent inhibitors for this enzyme. The authors have purified the enzyme to a >90% level from the recombinant Escherichia coli strain YMC21E, and it was used for partial characterization as well as standardization experiments. The results indicated that the Kmof the enzyme for L-glutamine and hydroxylamine were 60 mM and 8.3 mM, respectively. The Km for ADP, arsenate, and Mn2+ were 2 [.proportional]M, 5 [.proportional]M, and 25 [.proportional]M, respectively. When the components were adjusted according to their Km values, the activity remained constant for at least 3 h at both 25° C and 37° C. The Z′ factor determined in microplate format indicated robustness of the assay. When the signal/noise ratios were determined for different assay volumes, it was observed that the 200-[.proportional]l volume was found to be optimum. The DMSO tolerance of the enzyme was checked up to 10%, with minimal inhibition. The IC50 value determined for L-methionine S-sulfoximine on the enzyme activity was 3 mM. Approximately 18,000 small molecules could be screened per day using this protocol by a Beckman Coulter HTS setup.

High-throughput screening in the diagnostics industry

2002 ◽  
Vol 30 (4) ◽  
pp. 794-797 ◽  
Author(s):  
S. Wilson ◽  
S. Howell
Keyword(s):  
Product Development ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rapid Identification ◽  
Target Antigen ◽  
Cycle Times ◽  
Development Cycle ◽  
Speed Up ◽  
Product Development Cycle ◽  
Automated Screening

The diagnostics industry is constantly under pressure to bring innovation quicker to market and so the impetus to speed up product-development cycle times becomes greater. There are a number of steps in the product-development cycle where the application of high-throughput screening can help. In the case of lateral-flow immunodiagnostics the selection of antibody reagents is paramount. In particular, rapid identification of antibody pairs that are able to ‘sandwich’ around the target antigen is required. One screen that has been applied successfully is the use of surface plasmon resonance biosensors like Biacore®. Using such a system one can evaluate over 400 antibody pairings in under 5 days. Conventional approaches to screen this number of antibody pairs would take many months. Other automated screening systems like DELFIA® can be used in processing the vast amount of tests required for clinical trials. In addition, the use of robotics to automate routine product testing can be used to shorten the product-development cycle.

scholarly journals Fluorescence Detection-Based Functional Assay for High-Throughput Screening for MraY

2004 ◽  
Vol 48 (3) ◽  
pp. 897-902 ◽  
Author(s):  
Thérèse Stachyra ◽  
Christophe Dini ◽  
Paul Ferrari ◽  
Ahmed Bouhss ◽  
Jean van Heijenoort ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Pressure ◽  
Cell Wall ◽  
High Throughput ◽  
High Throughput Screening ◽  
Reaction Medium ◽  
The Other ◽  
Functional Assay ◽  
Liquid Chromatography Separation ◽  
Fluorescent Derivative

ABSTRACT We have developed a novel assay specific to MraY, which catalyzes the first membrane step in the biosynthesis of bacterial cell wall peptidoglycan. This was accomplished by using UDP-MurNAc-Nε -dansylpentapeptide, a fluorescent derivative of the MraY nucleotide substrate, and a partially purified preparation of MraY solubilized from membranes of an Escherichia coli overproducing strain. Two versions of the assay were developed, one consisting of the high-pressure liquid chromatography separation of the substrate and product (dansylated lipid I) and the other, without separation and adapted to the high-throughput format, taking advantage of the different fluorescence properties of the nucleotide and lipid I in the reaction medium. The latter assay was validated with a set of natural and synthetic MraY inhibitors.

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