ACS Combinatorial Science最新文献

{"title":"Design and Combinatorial Development of Shield-1 Peptide Mimetics Binding to Destabilized FKBP12","authors":"Daniel Madsen,&nbsp;Frederik P. Jørgensen,&nbsp;Daniel Palmer,&nbsp;Milena E. Roux,&nbsp;Jakob V. Olsen,&nbsp;Mikael Bols,&nbsp;Sanne Schoffelen,&nbsp;Frederik Diness*,&nbsp;Morten Meldal*","doi":"10.1021/acscombsci.9b00197","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00197","url":null,"abstract":"<p >On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA₁₉₀₀ beads consisting of small tripeptides with a triazole-capped <i>N</i>-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"1476793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PTML Model of ChEMBL Compounds Assays for Vitamin Derivatives","authors":"Ricardo Santana*,&nbsp;Robin Zuluaga,&nbsp;Piedad Gañán,&nbsp;Sonia Arrasate,&nbsp;Enrique Onieva Caracuel,&nbsp;Humbert González-Díaz*","doi":"10.1021/acscombsci.9b00166","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00166","url":null,"abstract":"<p >Determining the biological activity of vitamin derivatives is needed given that organic synthesis of analogs of vitamins is an active field of interest for medicinal chemistry, pharmaceuticals, and food additives. Accordingly, scientists from different disciplines perform preclinical assays (<i>n</i>_<i>ij</i>) with a considerable combination of assay conditions (<b>c</b>_<i>j</i>). Indeed, the ChEMBL platform contains a database that includes results from 36?220 different biological activity bioassays of 21?240 different vitamins and vitamin derivatives. These assays present are heterogeneous in terms of assay combinations of <b>c</b>_<i>j</i>. They are focused on &gt;500 different biological activity parameters (<i>c</i>₀), &gt;340 different targets (<i>c</i>₁), &gt;6200 types of cell (<i>c</i>₂), &gt;120 organisms of assay (<i>c</i>₃), and &gt;60 assay strains (<i>c</i>₄). It includes a total of &gt;1850 niacin assays, &gt;1580 tretinoin assays, &gt;1580 retinol assays, 857 ascorbic acid assays, etc. Given the complexity of this combinatorial data in terms of being assimilated by researchers, we propose to build a model by combining perturbation theory (PT) and machine learning (ML). Through this study, we propose a PTML (PT + ML) combinatorial model for ChEMBL results on biological activity of vitamins and vitamins derivatives. The linear discriminant analysis (LDA) model presented the following results for training subset a: specificity (%) = 90.38, sensitivity (%) = 87.51, and accuracy (%) = 89.89. The model showed the following results for the external validation subset: specificity (%) = 90.58, sensitivity (%) = 87.72, and accuracy (%) = 90.09. Different types of linear and nonlinear PTML models, such as logistic regression (LR), classification tree (CT), n?ive Bayes (NB), and random Forest (RF), were applied to contrast the capacity of prediction. The PTML-LDA model predicts with more accuracy by applying combinatorial descriptors. In addition, a PCA experiment with chemical structure descriptors allowed us to characterize the high structural diversity of the chemical space studied. In any case, PTML models using chemical structure descriptors do not improve the performance of the PTML-LDA model based on ALOGP and PSA. We can conclude that the three variable PTML-LDA model is a simplified and adaptable tool for the prediction, for different experiment combinations, the biological activity of derivative vitamins.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"463915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incorporation of Fluorine into an OBOC Peptide Library by Copper-Free Click Chemistry toward the Discovery of PET Imaging Agents","authors":"Emily Murrell,&nbsp;Leonard G. Luyt*","doi":"10.1021/acscombsci.9b00146","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00146","url":null,"abstract":"<p >A one-bead one-compound (OBOC) library of peptide-based imaging agents was developed where a ¹⁹F-containing moiety was added onto the N-terminus of octamer peptides through copper-free click chemistry prior to screening of the library. This created a library of complete imaging agents that was screened against CXCR4, a receptor of interest for cancer imaging. The screen directly resulted in the discovery of a peptide-based imaging agent with an IC₅₀ of 138 μM. This proof-of-concept study describes a new type of OBOC peptide library design, where hits discovered from screening can be easily translated into their fluorine-18 counterpart for PET imaging without loss of affinity.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"462658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aerobic Oxidation of Alcohols Catalyzed by in Situ Generated Gold Nanoparticles inside the Channels of Periodic Mesoporous Organosilica with Ionic Liquid Framework","authors":"Babak Karimi*,&nbsp;Akram Bigdeli,&nbsp;Ali Asghar Safari,&nbsp;Mojtaba Khorasani,&nbsp;Hojatollah Vali,&nbsp;Somaiyeh Khodadadi Karimvand","doi":"10.1021/acscombsci.9b00160","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00160","url":null,"abstract":"<p ><i>In situ</i> generated gold nanoparticles inside the nanospaces of periodic mesoporous organosilica with an imidazolium framework ([email?protected]) were found to be highly active, selective, and reusable catalysts for the aerobic oxidation of activated and nonactivated alcohols under mild reaction conditions. The catalyst was characterized by nitrogen adsorption–desorption measurement, thermogravimetric analysis (TGA), transmission electron microscopy (TEM), elemental analysis (EA), diffuse reflectance infrared Fourier transform spectroscopy (DRIFT), X-ray photoelectron spectroscopy (XPS), and inductively coupled plasma atomic emission spectroscopy (ICP-AES). The catalyst exhibited excellent catalytic activity in the presence of either Cs₂CO₃ (35 °C) or K₂CO₃ (60 °C) as reaction bases in toluene as a reaction solvent. Under both reaction conditions, various types of alcohols (up to 35 examples) including activated benzylic, primary and secondary aliphatic, heterocyclic, and challenging cyclic aliphatic alcohols converted to the expected carbonyl compounds in good to excellent yields and selectivity. The catalyst was also recovered and reused for at least seven reaction cycles. Data from three independent leaching tests indicated that amounts of leached gold particles were negligible (&lt;0.2 ppm). It is believed that the combination of bridged imidazolium groups and confined nanospaces of PMO-IL might be a major reason explaining the remarkable stabilization and homogeneous distribution of in situ generated gold nanoparticles, thus resulting in the highly active and recyclable catalyst system.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00160","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"544181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Denoising DNA Encoded Library Screens with Sparse Learning.","authors":"Péter Kómár, M. Kalinić","doi":"10.26434/chemrxiv.11573427","DOIUrl":"https://doi.org/10.26434/chemrxiv.11573427","url":null,"abstract":"DNA-encoded libraries (DELs) are large, pooled collections of compounds in which every library member is attached to a stretch of DNA encoding its complete synthetic history. DEL-based hit discovery involves affinity selection of the library against a protein of interest, whereby compounds retained by the target are subsequently identified by next-generation sequencing of the corresponding DNA tags. When analyzing the resulting data, one typically assumes that sequencing output (i.e. read counts) is proportional to the binding affinity of a given compound, thus enabling hit prioritization and elucidation of any underlying structure-activity relationships (SAR). This assumption, though, tends to be severely confounded by a number of factors, including variable reaction yields, presence of incomplete products masquerading as their intended counterparts, and sequencing noise. In practice, these confounders are often ignored, potentially contributing to low hit validation rates, and universally leading to loss of valuable information. To address this issue, we have developed a method for comprehensively denoising DEL selection outputs. Our method, dubbed \"deldenoiser\", is based on sparse learning and leverages inputs that are commonly available within a DEL generation and screening workflow. Using simulated and publicly available DEL affinity selection data, we show that \"deldenoiser\" is not only able to recover and rank true binders much more robustly than read count-based approaches, but also that it yields scores which accurately capture the underlying SAR. The proposed method can, thus, be of significant utility in hit prioritization following DEL screens.","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84050239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homogeneous and Functional Group Tolerant Ring-Closing Metathesis for DNA-Encoded Chemical Libraries","authors":"Olivier B. C. Monty,&nbsp;Pranavanand Nyshadham,&nbsp;Kurt M. Bohren,&nbsp;Murugesan Palaniappan,&nbsp;Martin M. Matzuk,&nbsp;Damian W. Young*,&nbsp;Nicholas Simmons*","doi":"10.1021/acscombsci.9b00199","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00199","url":null,"abstract":"<p >Reaction heterogeneity, poor pH control, and catalyst decomposition in the ring-closing metathesis (RCM) of DNA–chemical conjugates lead to poor yields of the cyclized products. Herein we address these issues with a RCM reaction system that includes a novel aqueous solvent combination to enable reaction homogeneity, an acidic buffer system which masks traditionally problematic functional groups, and a decomposition-resistant catalyst which maximizes conversion to the cyclized product. Additionally, we provide a systematic study of the substrate scope of the on-DNA RCM reaction, a demonstration of its applicability to a single-substrate DNA-encoded chemical library that includes sequencing analysis, and the first successful stapling of an unprotected on-DNA [i, i+4] peptide.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"609327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiproliferative Activities of Diimine-Based Mixed Ligand Copper(II) Complexes","authors":"Nazanin Kordestani,&nbsp;Hadi Amiri Rudbari*,&nbsp;Alexandra R. Fernandes*,&nbsp;Luís R. Raposo,&nbsp;Pedro V. Baptista,&nbsp;Daniela Ferreira,&nbsp;Giuseppe Bruno,&nbsp;Giovanni Bella,&nbsp;Rosario Scopelliti,&nbsp;Jason D. Braun,&nbsp;David E. Herbert,&nbsp;Olivier Blacque","doi":"10.1021/acscombsci.9b00202","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00202","url":null,"abstract":"<p >A series of Cu(diimine)(X-sal)(NO₃) complexes, where the diimine is either 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen) and X-sal is a monoanionic halogenated salicylaldehyde (X = Cl, Br, I, or H), have been synthesized and characterized by elemental analysis and X-ray crystallography. Penta-coordinate geometries copper(II) were observed for all cases. The influence of the diimine coligands and different halogen atoms on the antiproliferative activities toward human cancer cell lines have been investigated. All Cu(II) complexes were able to induce a loss of A2780 ovarian carcinoma cell viability, with phen derivatives more active than bpy derivatives. In contrast, no in vitro antiproliferative effects were observed against the HCT116 colorectal cancer cell line. These cytotoxicity differences were not due to a different intracellular concentration of the complexes determined by inductively coupled plasma atomic emission spectroscopy. A small effect of different halogen substituents on the phenolic ring was observed, with X = Cl being the most highly active toward A2780 cells among the phen derivatives, while X = Br presented the lowest IC₅₀ in A2780 cells for bpy analogs. Importantly, no reduction in normal primary fibroblasts cell viability was observed in the presence of bpy derivatives (IC₅₀ &gt; 40 μM). Mechanistically, complex <b>1</b> seems to induce a stronger apoptotic response with a higher increase in mitochondrial membrane depolarization and an increased level of intracellular reactive oxygen species (ROS) compared to complex <b>3</b>. Together, these data and the low IC₅₀ compared to cisplatin in A2780 ovarian carcinoma cell line demonstrate the potential of these bpy derivatives for further in vivo studies.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"609326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxidative Cyclization Approach to Benzimidazole Libraries","authors":"Eric P. Arnold,&nbsp;Prolay K. Mondal,&nbsp;Daniel C. Schmitt*","doi":"10.1021/acscombsci.9b00189","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00189","url":null,"abstract":"<p >An efficient approach to the parallel synthesis of benzimidazoles from anilines is described. Library approaches to vary the N1 and C2 vectors of benzimidazoles are well established; however, C4–C7 variation has traditionally relied on 1,2-dianiline building blocks, providing limited chemical space coverage. We have developed an amidine formation/oxidative cyclization sequence that enables anilines as a diversity set for benzimidazole C4–C7 SAR generation in parallel format. The amidine annulation was achieved using PIDA or Cu-mediated oxidation to access both N–H and N–alkyl benzimidazoles. This library protocol has now been utilized for analog production in four medicinal chemistry projects. Additionally, the synthesis of aza-benzimidazoles from aminopyridines was achieved via an analogous sequence.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2019-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"293021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of an Automatic, High-Throughput Structural Refinement Method Using Rietveld Analysis","authors":"Akihisa Aimi*,&nbsp;Kenjiro Fujimoto","doi":"10.1021/acscombsci.9b00158","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00158","url":null,"abstract":"<p >Automated structural analysis techniques are required to accelerate materials research. In this study, we developed an algorithm to automate Rietveld analysis, which is a method for crystal structure refinement using powder diffraction patterns. This algorithm features the repeated generation of a set of initial values, followed by one-shot refinement. Accurate results were obtained without any strategy for the sequence of refinement, as is often used in manual analysis. Implementation and testing of the automated algorithm provided fitting results that were comparable to those of manual analysis, even when inaccurate initial values for structural parameters were input. Moreover, the much shorter time was required for the developed automatic analysis method than for manual analysis. The developed method will likely facilitate the analysis of large amounts of diffraction data, allowing the accumulation of structural data that can enhance the efficacy of materials research.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2019-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00158","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"276545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Off-DNA DNA-Encoded Library Affinity Screening","authors":"Amber L. Hackler,&nbsp;Forrest G. FitzGerald,&nbsp;Vuong Q. Dang,&nbsp;Alexander L. Satz,&nbsp;Brian M. Paegel*","doi":"10.1021/acscombsci.9b00153","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00153","url":null,"abstract":"<p >DNA-encoded library (DEL) technology is emerging as a key element of the small molecule discovery toolbox. Conventional DEL screens (i.e., on-DNA screening) interrogate large combinatorial libraries via affinity selection of DNA-tagged library members that are ligands of a purified and immobilized protein target. In these selections, the DNA tags can materially and undesirably influence target binding and, therefore, the experiment outcome. Here, we use a solid-phase DEL and droplet-based microfluidic screening to separate the DEL member from its DNA tag (i.e., off-DNA screening), for subsequent in-droplet laser-induced fluorescence polarization (FP) detection of target binding, obviating DNA tag interference. Using the receptor tyrosine kinase (RTK) discoidin domain receptor 1 (DDR1) as a proof-of-concept target in a droplet-scale competition-binding assay, we screened a 67?100-member solid-phase DEL of drug-like small molecules for competitive ligands of DDR1 and identified several known RTK inhibitor pharmacophores, including azaindole- and quinazolinone-containing monomers. Off-DNA DEL affinity screening with FP detection is potentially amenable to a wide array of target classes, including nucleic acid binding proteins, proteins that are difficult to overexpress and purify, or targets with no known activity assay.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2019-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00153","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"290001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}