Publications by authors named "Yurii S Moroz"

52 Publications

One-pot parallel synthesis of 1,3,5-trisubstituted 1,2,4-triazoles.

Mol Divers 2021 Apr 2. Epub 2021 Apr 2.

Enamine Ltd., Chervonotkatska Street 78, Kyiv, 02094, Ukraine.

An implementation of the three-component one-pot approach to unsymmetrical 1,3,5-trisubstituted-1,2,4-triazoles into combinatorial chemistry is described. The procedure is based on the coupling of amidines with carboxylic acids and subsequent cyclization with hydrazines. After the preliminary assessment of the reagent scope, the method had 81% success rate in parallel synthesis. It was shown that over a billion-sized chemical space of readily accessible ("REAL") compounds may be generated based on the proposed methodology. Analysis of physicochemical parameters shows that the library contains significant fractions of both drug-like and "beyond-rule-of-five" members. More than 10 million of accessible compounds meet the strictest lead-likeness criteria. Additionally, 195 Mln of sp-enriched compounds can be produced. This makes the proposed approach a valuable tool in medicinal chemistry.
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http://dx.doi.org/10.1007/s11030-021-10218-2DOI Listing
April 2021

SAVI, in silico generation of billions of easily synthesizable compounds through expert-system type rules.

Sci Data 2020 11 11;7(1):384. Epub 2020 Nov 11.

Computer-Aided Drug Design Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.

We have made available a database of over 1 billion compounds predicted to be easily synthesizable, called Synthetically Accessible Virtual Inventory (SAVI). They have been created by a set of transforms based on an adaptation and extension of the CHMTRN/PATRAN programming languages describing chemical synthesis expert knowledge, which originally stem from the LHASA project. The chemoinformatics toolkit CACTVS was used to apply a total of 53 transforms to about 150,000 readily available building blocks (enamine.net). Only single-step, two-reactant syntheses were calculated for this database even though the technology can execute multi-step reactions. The possibility to incorporate scoring systems in CHMTRN allowed us to subdivide the database of 1.75 billion compounds in sets according to their predicted synthesizability, with the most-synthesizable class comprising 1.09 billion synthetic products. Properties calculated for all SAVI products show that the database should be well-suited for drug discovery. It is being made publicly available for free download from https://doi.org/10.35115/37n9-5738.
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http://dx.doi.org/10.1038/s41597-020-00727-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658252PMC
November 2020

Generating Multibillion Chemical Space of Readily Accessible Screening Compounds.

iScience 2020 Nov 15;23(11):101681. Epub 2020 Oct 15.

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

An approach to the generation of ultra-large chemical libraries of readily accessible ("REAL") compounds is described. The strategy is based on the use of two- or three-step three-component reaction sequences and available starting materials with pre-validated chemical reactivity. After the preliminary parallel experiments, the methods with at least ∼80% synthesis success rate (such as acylation - deprotection - acylation of monoprotected diamines or amide formation - click reaction with functionalized azides) can be selected and used to generate the target chemical space. It is shown that by using only on the two aforementioned reaction sequences, a nearly 29-billion compound library is easily obtained. According to the predicted physico-chemical descriptor values, the generated chemical space contains large fractions of both drug-like and "beyond rule-of-five" members, whereas the strictest lead-likeness criteria (the so-called Churcher's rules) are met by the lesser part, which still exceeds 22 million.
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http://dx.doi.org/10.1016/j.isci.2020.101681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593547PMC
November 2020

ZINC20-A Free Ultralarge-Scale Chemical Database for Ligand Discovery.

J Chem Inf Model 2020 12 29;60(12):6065-6073. Epub 2020 Oct 29.

NextMove Software Ltd, Innovation Centre, 320 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, United Kingdom.

Identifying and purchasing new small molecules to test in biological assays are enabling for ligand discovery, but as purchasable chemical space continues to grow into the tens of billions based on inexpensive make-on-demand compounds, simply searching this space becomes a major challenge. We have therefore developed ZINC20, a new version of ZINC with two major new features: billions of new molecules and new methods to search them. As a fully enumerated database, ZINC can be searched precisely using explicit atomic-level graph-based methods, such as SmallWorld for similarity and Arthor for pattern and substructure search, as well as 3D methods such as docking. Analysis of the new make-on-demand compound sets by these and related tools reveals startling features. For instance, over 97% of the core Bemis-Murcko scaffolds in make-on-demand libraries are unavailable from "in-stock" collections. Correspondingly, the number of new Bemis-Murcko scaffolds is rising almost as a linear fraction of the elaborated molecules. Thus, an 88-fold increase in the number of molecules in the make-on-demand versus the in-stock sets is built upon a 16-fold increase in the number of Bemis-Murcko scaffolds. The make-on-demand library is also more structurally diverse than physical libraries, with a massive increase in disc- and sphere-like shaped molecules. The new system is freely available at zinc20.docking.org.
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http://dx.doi.org/10.1021/acs.jcim.0c00675DOI Listing
December 2020

An open-source drug discovery platform enables ultra-large virtual screens.

Nature 2020 04 9;580(7805):663-668. Epub 2020 Mar 9.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard University, Boston, MA, USA.

On average, an approved drug currently costs US$2-3 billion and takes more than 10 years to develop. In part, this is due to expensive and time-consuming wet-laboratory experiments, poor initial hit compounds and the high attrition rates in the (pre-)clinical phases. Structure-based virtual screening has the potential to mitigate these problems. With structure-based virtual screening, the quality of the hits improves with the number of compounds screened. However, despite the fact that large databases of compounds exist, the ability to carry out large-scale structure-based virtual screening on computer clusters in an accessible, efficient and flexible manner has remained difficult. Here we describe VirtualFlow, a highly automated and versatile open-source platform with perfect scaling behaviour that is able to prepare and efficiently screen ultra-large libraries of compounds. VirtualFlow is able to use a variety of the most powerful docking programs. Using VirtualFlow, we prepared one of the largest and freely available ready-to-dock ligand libraries, with more than 1.4 billion commercially available molecules. To demonstrate the power of VirtualFlow, we screened more than 1 billion compounds and identified a set of structurally diverse molecules that bind to KEAP1 with submicromolar affinity. One of the lead inhibitors (iKeap1) engages KEAP1 with nanomolar affinity (dissociation constant (K) = 114 nM) and disrupts the interaction between KEAP1 and the transcription factor NRF2. This illustrates the potential of VirtualFlow to access vast regions of the chemical space and identify molecules that bind with high affinity to target proteins.
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http://dx.doi.org/10.1038/s41586-020-2117-zDOI Listing
April 2020

Virtual discovery of melatonin receptor ligands to modulate circadian rhythms.

Nature 2020 03 10;579(7800):609-614. Epub 2020 Feb 10.

Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), The State University of New York, Buffalo, NY, USA.

The neuromodulator melatonin synchronizes circadian rhythms and related physiological functions through the actions of two G-protein-coupled receptors: MT and MT. Circadian release of melatonin at night from the pineal gland activates melatonin receptors in the suprachiasmatic nucleus of the hypothalamus, synchronizing the physiology and behaviour of animals to the light-dark cycle. The two receptors are established drug targets for aligning circadian phase to this cycle in disorders of sleep and depression. Despite their importance, few in vivo active MT-selective ligands have been reported, hampering both the understanding of circadian biology and the development of targeted therapeutics. Here we docked more than 150 million virtual molecules to an MT crystal structure, prioritizing structural fit and chemical novelty. Of these compounds, 38 high-ranking molecules were synthesized and tested, revealing ligands with potencies ranging from 470 picomolar to 6 micromolar. Structure-based optimization led to two selective MT inverse agonists-which were topologically unrelated to previously explored chemotypes-that acted as inverse agonists in a mouse model of circadian re-entrainment. Notably, we found that these MT-selective inverse agonists advanced the phase of the mouse circadian clock by 1.3-1.5 h when given at subjective dusk, an agonist-like effect that was eliminated in MT- but not in MT-knockout mice. This study illustrates the opportunities for modulating melatonin receptor biology through MT-selective ligands and for the discovery of previously undescribed, in vivo active chemotypes from structure-based screens of diverse, ultralarge libraries.
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http://dx.doi.org/10.1038/s41586-020-2027-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134359PMC
March 2020

Kemp Eliminases of the AlleyCat Family Possess High Substrate Promiscuity.

ChemCatChem 2019 Mar 15;11(5):1425-1430. Epub 2019 Jan 15.

Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY 13244, USA.

Minimalist enzymes designed to catalyze model reactions provide useful starting points for creating catalysts for practically important chemical transformations. We have shown that Kemp eliminases of the AlleyCat family facilitate conversion of leflunomide (an immunosupressor pro-drug) to its active form teriflunomide with outstanding rate enhancement (nearly four orders of magnitude) and catalytic proficiency (more than seven orders of magnitude) without any additional optimization. This remarkable activity is achieved by properly positioning the substrate in close proximity to the catalytic glutamate with very high pK.
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http://dx.doi.org/10.1002/cctc.201801994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884320PMC
March 2019

Regioselective Synthesis of Functionalized 3- or 5-Fluoroalkyl Isoxazoles and Pyrazoles from Fluoroalkyl Ynones and Binucleophiles.

J Org Chem 2019 12 8;84(23):15212-15225. Epub 2019 Nov 8.

Enamine Ltd. , Chervonotkatska Street 78 , Kyiv 02094 , Ukraine.

A facile synthetic route toward either 3- or 5-fluoroalkyl-substituted isoxazoles or pyrazoles containing an additional functionalization site was developed and applied on a multigram scale. The elaborated approach extends the scope of fluoroalkyl substituents for introduction into the heterocyclic moiety, and uses convenient transformations of the side chain for incorporation of fluoroalkyl-substituted azoles into the structures of biologically active molecules. The utility of the obtained building blocks for isosteric replacement of alkyl-substituted isoxazole and pyrazole was shown by the synthesis of fluorinated Isocarboxazid and Mepiprazole analogues.
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http://dx.doi.org/10.1021/acs.joc.9b02258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310498PMC
December 2019

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes.

J Org Chem 2019 12 30;84(24):15877-15899. Epub 2019 Oct 30.

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

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert-Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.
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http://dx.doi.org/10.1021/acs.joc.9b02264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341682PMC
December 2019

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

One-Pot Parallel Synthesis of 5-(Dialkylamino)tetrazoles.

ACS Comb Sci 2019 09 29;21(9):635-642. Epub 2019 Aug 29.

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

Two protocols for the combinatorial synthesis of 5-(dialkylamino)tetrazoles were developed. The best success rate (67%) was shown by the method that used primary and secondary amines, 2,2,2-trifluoroethylthiocarbamate, and sodium azide as the starting reagents. The key steps included the formation of unsymmetrical thiourea, subsequent alkylation with 1,3-propane sultone and cyclization with azide anion. A 559-member aminotetrazole library was synthesized by this approach; the overall readily accessible (REAL) chemical space covered by the method exceeded 7 million feasible compounds.
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http://dx.doi.org/10.1021/acscombsci.9b00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297054PMC
September 2019

Ultra-large library docking for discovering new chemotypes.

Nature 2019 02 6;566(7743):224-229. Epub 2019 Feb 6.

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.

Despite intense interest in expanding chemical space, libraries containing hundreds-of-millions to billions of diverse molecules have remained inaccessible. Here we investigate structure-based docking of 170 million make-on-demand compounds from 130 well-characterized reactions. The resulting library is diverse, representing over 10.7 million scaffolds that are otherwise unavailable. For each compound in the library, docking against AmpC β-lactamase (AmpC) and the D dopamine receptor were simulated. From the top-ranking molecules, 44 and 549 compounds were synthesized and tested for interactions with AmpC and the D dopamine receptor, respectively. We found a phenolate inhibitor of AmpC, which revealed a group of inhibitors without known precedent. This molecule was optimized to 77 nM, which places it among the most potent non-covalent AmpC inhibitors known. Crystal structures of this and other AmpC inhibitors confirmed the docking predictions. Against the D dopamine receptor, hit rates fell almost monotonically with docking score, and a hit-rate versus score curve predicted that the library contained 453,000 ligands for the D dopamine receptor. Of 81 new chemotypes discovered, 30 showed submicromolar activity, including a 180-pM subtype-selective agonist of the D dopamine receptor.
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http://dx.doi.org/10.1038/s41586-019-0917-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383769PMC
February 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

Evolution of commercially available compounds for HTS.

Drug Discov Today 2019 02 3;24(2):390-402. Epub 2018 Nov 3.

Awridian Ltd, Gunnelswood Road, Stevenage SG1 2FX, UK. Electronic address:

Over recent years, an industry of compound suppliers has grown to provide drug discovery with screening compounds: it is estimated that there are over 16 million compounds available from these sources. Here, we review the chemical space covered by suppliers' compound libraries (SCL) in terms of compound physicochemical properties, novelty, diversity, and quality. We examine the feasibility of compiling high-quality vendor-based libraries avoiding complicated, expensive compound management activity, and compare the resulting libraries to the ChEMBL data set. We also consider how vendors have responded to the evolving requirements for drug discovery.
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http://dx.doi.org/10.1016/j.drudis.2018.10.016DOI Listing
February 2019

(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

Copper-Containing Catalytic Amyloids Promote Phosphoester Hydrolysis and Tandem Reactions.

ACS Catal 2018 Jan 22;8(1):59-62. Epub 2017 Nov 22.

Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY 13244.

Self-assembly of short de novo designed peptides gives rise to catalytic amyloids capable of facilitating multiple chemical transformations. We show that catalytic amyloids can efficiently hydrolyze paraoxon, a widely used, highly toxic organophosphate pesticide. Moreover, these robust and inexpensive metal-containing materials can be easily deposited on various surfaces producing catalytic flow devices. Finally, functional promiscuity of catalytic amyloids promotes tandem hydrolysis/oxidation reactions. High efficiency discovered in a very small library of peptides suggests an enormous potential for further improvement of catalytic properties both in terms of catalytic efficiency and substrate scope.
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http://dx.doi.org/10.1021/acscatal.7b03323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181230PMC
January 2018

Facile One-Pot Parallel Synthesis of 3-Amino-1,2,4-triazoles.

ACS Comb Sci 2018 07 18;20(7):461-466. Epub 2018 Jun 18.

Enamine, Ltd. , 78 Chervonotkatska Street , Kyiv , 02094 , Ukraine.

A 1,2,4-triazole motif is present in numerous commercialized and investigational bioactive molecules. Despite its importance for medicinal chemistry, there is a lack of convenient combinatorial approaches toward this molecular core. Herein, we present a synthetic strategy suitable for the quick preparation of a library of structurally diverse 1,2,4-triazoles in a one-pot setting. The key steps include the formation of thioureas followed by S-alkylation using 1,3-propane sultone and consecutive ring closure leading to the desired 1,2,4-triazoles. Parallel synthesis yields thousands of 1,2,4-triazoles in a cost- and time-efficient manner from commercially available chemicals.
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http://dx.doi.org/10.1021/acscombsci.8b00060DOI Listing
July 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

Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting-Group-Free Synthesis of Sulfonamides.

Chemistry 2018 Jun 29;24(33):8343-8349. Epub 2018 May 29.

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

Cyclic saturated aminosulfonyl fluorides were synthesized as their HCl salts. The compounds were found to be stable upon storage and could be used for the protecting-group-free synthesis of sulfonamides. In the presence of the -SO F group, the nitrogen atom could be modified by means of acylation, arylation, or reductive amination to give products that have high potential for the synthesis of bioactive compounds.
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http://dx.doi.org/10.1002/chem.201801140DOI Listing
June 2018

An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries.

ACS Comb Sci 2018 01 27;20(1):35-43. Epub 2017 Dec 27.

Enamine Ltd. , 78 Chervonotkatska Street, Kyiv 02094, Ukraine.

An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and α-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings.
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http://dx.doi.org/10.1021/acscombsci.7b00163DOI Listing
January 2018

Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles.

ACS Comb Sci 2016 10 7;18(10):616-624. Epub 2016 Sep 7.

ChemBioCenter, Kyiv National Taras Shevchenko University , 61 Chervonotkatska Street, Kyiv, 02094, Ukraine.

One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1. A library of 4 948 100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.
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http://dx.doi.org/10.1021/acscombsci.6b00103DOI Listing
October 2016

New Tricks for Old Proteins: Single Mutations in a Nonenzymatic Protein Give Rise to Various Enzymatic Activities.

J Am Chem Soc 2015 Dec 20;137(47):14905-11. Epub 2015 Nov 20.

Department of Chemistry, Syracuse University , 111 College Place, Syracuse, New York 13244, United States.

Design of a new catalytic function in proteins, apart from its inherent practical value, is important for fundamental understanding of enzymatic activity. Using a computationally inexpensive, minimalistic approach that focuses on introducing a single highly reactive residue into proteins to achieve catalysis we converted a 74-residue-long C-terminal domain of calmodulin into an efficient esterase. The catalytic efficiency of the resulting stereoselective, allosterically regulated catalyst, nicknamed AlleyCatE, is higher than that of any previously reported de novo designed esterases. The simplicity of our design protocol should complement and expand the capabilities of current state-of-art approaches to protein design. These results show that even a small nonenzymatic protein can efficiently attain catalytic activities in various reactions (Kemp elimination, ester hydrolysis, retroaldol reaction) as a result of a single mutation. In other words, proteins can be just one mutation away from becoming entry points for subsequent evolution.
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http://dx.doi.org/10.1021/jacs.5b07812DOI Listing
December 2015

2,2,2-Trifluoroethyl Chlorooxoacetate--Universal Reagent for One-Pot Parallel Synthesis of N(1)-Aryl-N(2)-alkyl-Substituted Oxamides.

ACS Comb Sci 2015 Oct 14;17(10):615-22. Epub 2015 Sep 14.

Enamine, Ltd. , 78 Chervonotkatska Street, Kyiv, 02094, Ukraine.

A one-pot parallel synthesis of N(1)-aryl-N(2)-alkyl-substituted oxamides with 2,2,2-trifluoroethyl chlorooxoacetate was developed. The synthesis of a library of 45 oxamides revealed higher efficiency of this reagent over the known ethyl chlorooxoacetate. The reagent was successfully used to prepare the known oxamide-containing HIV entry inhibitors.
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http://dx.doi.org/10.1021/acscombsci.5b00091DOI Listing
October 2015

One-Pot Parallel Synthesis of Alkyl Sulfides, Sulfoxides, and Sulfones.

ACS Comb Sci 2015 Jun 13;17(6):348-54. Epub 2015 May 13.

†Enamine, Ltd., 61 Chervonotkatska Street, Kyiv, 02094, Ukraine.

A simple and cost-effective one-pot parallel synthesis approach to sulfides, sulfoxides, and sulfones from thiourea was elaborated. The method combines two procedures optimized to the parallel synthesis conditions: alkylation of thiourea with alkyl chlorides and mono or full oxidation of in situ generated sulfides with H2O2 or H2O2-(NH4)2MoO4. The experimental set up required commonly used lab equipment: conventional oven and ultrasonic bath; the work up includes filtration or extraction with chloroform. The method was evaluated on an 81 member library of drug-like sulfides, sulfoxides, and sulfones yielding the compounds on a 30-300 mg scale. A small-scale synthesis of 2-(benzhydrylsulfinyl)acetamide (modafinil) utilizing our approach resulted in similar efficiency to the published procedures.
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http://dx.doi.org/10.1021/acscombsci.5b00024DOI Listing
June 2015

Functional characterization of a melittin analog containing a non-natural tryptophan analog.

Biopolymers 2015 Jul;104(4):384-394

Department of Chemistry and Biochemistry, Rowan University, Glassboro NJ 08028.

Tryptophan (Trp) is a naturally occurring amino acid, which exhibits fluorescence emission properties that are dependent on the polarity of the local environment around the Trp side chain. However, this sensitivity also complicates interpretation of fluorescence emission data. A non-natural analogue of tryptophan, β-(1-azulenyl)-L-alanine, exhibits fluorescence insensitive to local solvent polarity and does not impact the structure or characteristics of several peptides examined. In this study, we investigated the effect of replacing Trp with β-(1-azulenyl)-L-alanine in the well-known bee-venom peptide melittin. This peptide provides a model framework for investigating the impact of replacing Trp with β-(1-azulenyl)-L-alanine in a functional peptide system that undergoes significant shifts in Trp fluorescence emission upon binding to lipid bilayers. Microbiological methods including assessment of the antimicrobial activity by minimal inhibitory concentration (MIC) assays and bacterial membrane permeability assays indicated little difference between the Trp and the β-(1-azulenyl)-L-alanine-substituted versions of melittin. Circular dichroism spectroscopy showed both that peptides adopted the expected α-helical structures when bound to phospholipid bilayers and electrophysiological analysis indicated that both created membrane disruptions leading to significant conductance increases across model membranes. Both peptides exhibited a marked protection of the respective fluorophores when bound to bilayers indicating a similar membrane-bound topology. As expected, while fluorescence quenching and CD indicate the peptides are stably bound to lipid vesicles, the peptide containing β-(1-azulenyl)-L-alanine exhibited no fluorescence emission shift upon binding while the natural Trp exhibited >10 nm shift in emission spectrum barycenter. Taken together, the β-(1-azulenyl)-L-alanine can serve as a solvent insensitive alternative to Trp that does not have significant impacts on structure or function of membrane interacting peptides.
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http://dx.doi.org/10.1002/bip.22624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516667PMC
July 2015

β-(1-Azulenyl)-L-alanine--a functional probe for determination of pKa of histidine residues.

Chem Commun (Camb) 2015 Mar;51(25):5347-50

Department of Chemistry, Syracuse University, 111 College Place, Syracuse, NY 13244, USA.

β-(1-Azulenyl)-L-alanine (AzAla) can be incorporated into the influenza A virus M2 proton channel. AzAla's sensitivity to the protonation state of the nearby histidines and the lack of environmental fluorescence dependence allow for direct and straightforward determination of histidine pKa values in ion channels.
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http://dx.doi.org/10.1039/c4cc08720hDOI Listing
March 2015

Design of an allosterically regulated retroaldolase.

Protein Sci 2015 Apr 13;24(4):561-70. Epub 2015 Jan 13.

Department of Chemistry, Syracuse University, Syracuse, New York, 13244.

We employed a minimalist approach for design of an allosterically controlled retroaldolase. Introduction of a single lysine residue into the nonenzymatic protein calmodulin led to a 15,000-fold increase in the second order rate constant for retroaldol reaction with methodol as a substrate. The resulting catalyst AlleyCatR is active enough for subsequent directed evolution in crude cell bacterial lysates. AlleyCatR's activity is allosterically regulated by Ca(2+) ions. No catalysis is observed in the absence of the metal ion. The increase in catalytic activity originates from the hydrophobic interaction of the substrate (∼2000-fold) and the change in the apparent pKa of the active lysine residue.
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http://dx.doi.org/10.1002/pro.2622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380986PMC
April 2015

A one-pot parallel reductive amination of aldehydes with heteroaromatic amines.

ACS Comb Sci 2014 Aug 10;16(8):375-80. Epub 2014 Jul 10.

Enamine Ltd. , 23 Matrosova Street, Kyiv 01103, Ukraine.

A parallel reductive amination of heteroaromatic amines has been performed using a combination of ZnCl2-TMSOAc (activating agents) and NaBH(OAc)3 (reducing agent). A library of diverse secondary amines was easily prepared on a 50-300 mg scale.
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http://dx.doi.org/10.1021/co5000568DOI Listing
August 2014

2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel.

J Chem Phys 2014 Jun;140(23):235105

Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility of the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine-like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs.
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http://dx.doi.org/10.1063/1.4881188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098053PMC
June 2014