Publications by authors named "Petro Borysko"

13 Publications

  • Page 1 of 1

A prospective compound screening contest identified broader inhibitors for Sirtuin 1.

Sci Rep 2019 12 20;9(1):19585. Epub 2019 Dec 20.

Education Academy of Computational Life Sciences (ACLS), Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama, 226-8501, Japan.

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified.
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http://dx.doi.org/10.1038/s41598-019-55069-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925144PMC
December 2019

Screening of benzenesulfonamide in combination with chemically diverse fragments against carbonic anhydrase by differential scanning fluorimetry.

J Enzyme Inhib Med Chem 2020 Dec;35(1):306-310

Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy.

The differential scanning fluorimetry (DSF) screening of 5.692 fragments in combination with benzenesulfonamide (BSA) against bovine carbonic anhydrase (CA) delivered >100 hits that either caused, on their own, a significant thermal shift (Δ, °C) in the protein melting temperature or significantly influenced the thermal shift observed for BSA alone. Three hits based on 1,2,3-triazole moiety represent the periphery of the recently reported potent inhibitors of CA II, IX and XII which were efficacious . Such a re-discovery of suitable BSA periphery essentially validates the new fragment-based approach to the discovery of future CAIs. Structures of other validated fragment hits are reported.
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http://dx.doi.org/10.1080/14756366.2019.1698562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896451PMC
December 2020

Further validation of strecker-type α-aminonitriles as a new class of potent human carbonic anhydrase II inhibitors: hit expansion within the public domain using differential scanning fluorimetry leads to chemotype refinement.

J Enzyme Inhib Med Chem 2020 Dec;35(1):165-171

Neurofarba Department, Universita degli Studi di Firenze, Florence, Italy.

Testing of an expanded, 800-compound set of analogues of the earlier described Strecker-type α-aminonitriles (selected from publicly available Enamine Ltd. Screening Collection) in thermal shift assay against bovine carbonic anhydrase (CA) led to further validation of this new class of inhibitors and identification a new, refined chemotype represented by inhibitors with 10-improved potency. [Formula: see text].
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http://dx.doi.org/10.1080/14756366.2019.1693556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882446PMC
December 2020

SAR by Space: Enriching Hit Sets from the Chemical Space.

Molecules 2019 Aug 26;24(17). Epub 2019 Aug 26.

Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, 01601 Kyiv, Ukraine.

We introduce SAR-by-Space, a concept to drastically accelerate structure-activity relationship (SAR) elucidation by synthesizing neighboring compounds that originate from vast chemical spaces. The space navigation is accomplished within minutes on affordable standard computer hardware using a tree-based molecule descriptor and dynamic programming. Maximizing the synthetic accessibility of the results from the computer is achieved by applying a careful selection of building blocks in combination with suitably chosen reactions; a decade of in-house quality control shows that this is a crucial part in the process. The REAL Space is the largest chemical space of commercially available compounds, counting 11 billion molecules as of today. It was used to mine actives against bromodomain 4 (BRD4). Before synthesis, compounds were docked into the binding site using a scoring function, which incorporates intrinsic desolvation terms, thus avoiding time-consuming simulations. Five micromolecular hits have been identified and verified within less than six weeks, including the measurement of IC50 values. We conclude that this procedure is a substantial time-saver, accelerating both ligand- and structure-based approaches in hit generation and lead optimization stages.
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http://dx.doi.org/10.3390/molecules24173096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749418PMC
August 2019

Pros and cons of virtual screening based on public "Big Data": In silico mining for new bromodomain inhibitors.

Eur J Med Chem 2019 Mar 9;165:258-272. Epub 2019 Jan 9.

Laboratory of Chemoinformatics, Faculty of Chemistry, University of Strasbourg, 4, Blaise Pascal str, 67081, Strasbourg, France. Electronic address:

The Virtual Screening (VS) study described herein aimed at detecting novel Bromodomain BRD4 binders and relied on knowledge from public databases (ChEMBL, REAXYS) to establish a battery of predictive models of BRD activity for in silico selection of putative ligands. Beyond the actual discovery of new BRD ligands, this represented an opportunity to practically estimate the actual usefulness of public domain "Big Data" for robust predictive model building. Obtained models were used to virtually screen a collection of 2 million compounds from the Enamine company collection. This industrial partner then experimentally screened a subset of 2992 molecules selected by the VS procedure for their high likelihood to be active. Twenty nine confirmed hits were detected after experimental testing, representing 1% of the selected candidates. As a general conclusion, this study emphasizes once more that public structure-activity databases are nowadays key assets in drug discovery. Their usefulness is however limited by the state-of-the-art knowledge harvested so far by published studies. Target-specific structure-activity information is rarely rich enough, and its heterogeneity makes it extremely difficult to exploit in rational drug design. Furthermore, published affinity measures serving to build models selecting compounds to be experimentally screened may not be well correlated with the experimental hit selection criterion (in practice, often imposed by equipment constraints). Nevertheless, a robust 2.6-fold increase in hit rate with respect to an equivalent, random screening campaign showed that machine learning is able to extract some real knowledge in spite of all the noise in structure-activity data.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.010DOI Listing
March 2019

Photochemical In-Flow Synthesis of 2,4-Methanopyrrolidines: Pyrrolidine Analogues with Improved Water Solubility and Reduced Lipophilicity.

J Org Chem 2018 12 6;83(23):14350-14361. Epub 2018 Nov 6.

Enamine, Ltd. , Chervonotkatska 78 , Kyiv 02094 , Ukraine (www.enamine.net).

A practical synthesis of 2,4-methanopyrrolidines was elaborated. The key synthetic step was an intramolecular photochemical [2 + 2]-cycloaddition of an acrylic acid derivative in flow. In spite of a higher molecular weight, 2,4-methanopyrrolidines were shown to have higher solubility in water and lower lipophilicity than pyrrolidines, important characteristics of bioactive molecules in drug design.
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http://dx.doi.org/10.1021/acs.joc.8b02071DOI Listing
December 2018

(Chlorosulfonyl)benzenesulfonyl Fluorides-Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library.

ACS Comb Sci 2018 11 1;20(11):672-680. Epub 2018 Nov 1.

National Taras Shevchenko University of Kyiv, Volodymyrska Street 60 , Kyiv 01601 , Ukraine.

Multigram synthesis of (chlorosulfonyl)benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.
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http://dx.doi.org/10.1021/acscombsci.8b00130DOI Listing
November 2018

Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors.

Bioorg Med Chem 2018 07 9;26(12):3399-3405. Epub 2018 May 9.

Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine; National Taras Shevchenko University of Kyiv, Volodymyrska Street 60, Kyiv 01601, Ukraine. Electronic address:

A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC = 1.9-7.4 μM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking.
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http://dx.doi.org/10.1016/j.bmc.2018.05.010DOI Listing
July 2018

Synthesis of Multifunctional Spirocyclic Azetidines and Their Application in Drug Discovery.

Chemistry 2018 Apr 15;24(21):5444-5449. Epub 2018 Feb 15.

Enamine Ltd./Bienta, Chervonotkatska 78, 02094, Kyiv, Ukraine.

The synthesis of multifunctional spirocycles was achieved from common cyclic carboxylic acids (cyclobutane carboxylate, cyclopentane carboxylate, l-proline, etc.). The whole sequence included only two chemical steps-synthesis of azetidinones, and reduction into azetidines. The obtained spirocyclic amino acids were incorporated into a structure of the known anesthetic drug Bupivacaine. The obtained analogues were more active and less toxic than the original drug. We believe that this discovery will lead to a wide use of spirocyclic building blocks in drug discovery in the near future.
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http://dx.doi.org/10.1002/chem.201800193DOI Listing
April 2018

Photochemical Synthesis of 2-Azabicyclo[3.2.0]heptanes: Advanced Building Blocks for Drug Discovery. Synthesis of 2,3-Ethanoproline.

J Org Chem 2018 02 16;83(3):1394-1401. Epub 2018 Jan 16.

Enamine Ltd ., Chervonotkatska 78, Kyiv 02094, Ukraine , www.enamine.net.

Intramolecular photochemical [2 + 2]-cyclization of acetophenone enamides gave 2-azabicyclo[3.2.0]heptanes, advanced building blocks for drug discovery. Synthesis of a conformationally restricted analogue of proline, 2,3-ethanoproline, was performed.
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http://dx.doi.org/10.1021/acs.joc.7b02910DOI Listing
February 2018

Continued SAR exploration of 1,2,4-thiadiazole-containing scaffolds in the design of free fatty acid receptor 1 (GPR40) agonists.

Eur J Med Chem 2017 Nov 13;140:229-238. Epub 2017 Sep 13.

Molecular Therapeutics, School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Northern Ireland, UK.

An earlier reported series of 1,2,4-thiadiazole-based agonists of FFA1 (GPR40) was evolved into two structurally distinct series of compounds. One of the series (structurally related to known FFA1 agonist GW9508) displayed low micromolar potency while the other (representing a truncated version of the earlier reported potent FFA1 agonists) was, surprisingly, found to be devoid of agonist potency. In silico docking of representative compounds into the crystal structure of FFA1 revealed possible structural grounds for the observed SAR.
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http://dx.doi.org/10.1016/j.ejmech.2017.09.019DOI Listing
November 2017

An iterative compound screening contest method for identifying target protein inhibitors using the tyrosine-protein kinase Yes.

Sci Rep 2017 09 20;7(1):12038. Epub 2017 Sep 20.

Advanced Computational Drug Discovery Unit, Institute of Innovative Research, Tokyo Institute of Technology, J3-23 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.

We propose a new iterative screening contest method to identify target protein inhibitors. After conducting a compound screening contest in 2014, we report results acquired from a contest held in 2015 in this study. Our aims were to identify target enzyme inhibitors and to benchmark a variety of computer-aided drug discovery methods under identical experimental conditions. In both contests, we employed the tyrosine-protein kinase Yes as an example target protein. Participating groups virtually screened possible inhibitors from a library containing 2.4 million compounds. Compounds were ranked based on functional scores obtained using their respective methods, and the top 181 compounds from each group were selected. Our results from the 2015 contest show an improved hit rate when compared to results from the 2014 contest. In addition, we have successfully identified a statistically-warranted method for identifying target inhibitors. Quantitative analysis of the most successful method gave additional insights into important characteristics of the method used.
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http://dx.doi.org/10.1038/s41598-017-10275-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607274PMC
September 2017

Discovery of Strecker-type α-aminonitriles as a new class of human carbonic anhydrase inhibitors using differential scanning fluorimetry.

J Enzyme Inhib Med Chem 2016 Dec 16;31(6):1707-11. Epub 2016 Mar 16.

d Neurofarba Department, Universita degli Studi di Firenze , Florence , Italy.

A new type of carbonic anhydrase inhibitors was identified via differential scanning fluorimetry (DSF) screening. The compounds displayed interesting inhibition profile against human carbonic anhydrase isoforms I, II, IX and XII with an obvious selectivity displayed by one compound toward carbonic anhydrase (CA) IX, an established anti-cancer target. A hypothetical mechanism of inhibitory action by the Strecker-type α-aminonitriles has been proposed.
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http://dx.doi.org/10.3109/14756366.2016.1156676DOI Listing
December 2016