Identification of novel potential antibiotics against Staphylococcus using structure-based drug screening targeting dihydrofolate reductase.


:The emergence of multidrug-resistant Staphylococcus aureus (S. aureus) makes the treatment of infectious diseases in hospitals more difficult and increases the mortality of the patients. In this study, we attempted to identify novel potent antibiotic candidate compounds against S. aureus dihydrofolate reductase (saDHFR). We performed three-step in silico structure-based drug screening (SBDS) based on the crystal structure of saDHFR using a 154,118 chemical compound library. We subsequently evaluated whether candidate chemical compounds exhibited inhibitory effects on the growth of the model bacterium: Staphylococcus epidermidis (S. epidermidis). The compound KB1 showed a strong inhibitory effect on the growth of S. epidermidis. Moreover, we rescreened chemical structures similar to KB1 from a 461,397 chemical compound library. Three of the four KB1 analogs (KBS1, KBS3, and KBS4) showed inhibitory effects on the growth of S. epidermidis and enzyme inhibitory effects on saDHFR. We performed structure-activity relationship (SAR) analysis of active chemical compounds and observed a correlative relationship among the IC₅₀ values, interaction residues, and structure scaffolds. In addition, the active chemical compounds (KB1, KBS3, and KBS4) had no inhibitory effects on the growth of model enterobacteria (E. coli BL21 and JM109 strains) and no toxic effects on cultured mammalian cells (MDCK cells). Results obtained from Protein Ligand Interaction Fingerprint (PLIF) and Ligand Interaction (LI) analyses suggested that all of the active compounds exhibited potential inhibitory effects on mutated saDHFR of the drug-resistant strains. The structural and experimental information concerning these novel chemical compounds will likely contribute to the development of new antibiotics for both wild-type and drug-resistant S. aureus.


J Chem Inf Model


Kobayashi M,Kinjo T,Koseki Y,Bourne CR,Barrow WW,Aoki S




Has Abstract


2014-04-28 00:00:00












  • Metabotropic glutamate receptor-mediated currents at the climbing fiber to Purkinje cell synapse.

    abstract::Different forms of synaptic plasticity in the cerebellum expressed at the synapses onto Purkinje cells (PCs) are mediated by membrane metabotropic glutamate receptors (mGluRs). There are three main mGluR groups with a total of 8 subtypes. Although mGluRs are also found at the climbing fiber (CF) to PC synapses, the di...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Andjus PR,Bajić A,Zhu L,Strata P

    更新日期:2005-11-01 00:00:00

  • Secondary structure characterization based on amino acid composition and availability in proteins.

    abstract::The importance of thorough analyses of the secondary structures in proteins as basic structural units cannot be overemphasized. Although recent computational methods have achieved reasonably high accuracy for predicting secondary structures from amino acid sequences, a simple and fundamental empirical approach to char...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Otaki JM,Tsutsumi M,Gotoh T,Yamamoto H

    更新日期:2010-04-26 00:00:00

  • AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein-Protein Interaction Interfaces.

    abstract::Inhibition of protein-protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structura...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Rooklin D,Wang C,Katigbak J,Arora PS,Zhang Y

    更新日期:2015-08-24 00:00:00

  • HLA-DM Stabilizes the Empty MHCII Binding Groove: A Model Using Customized Natural Move Monte Carlo.

    abstract::MHC class II molecules bind peptides derived from extracellular proteins that have been ingested by antigen-presenting cells and display them to the immune system. Peptide loading occurs within the antigen-presenting cell and is facilitated by HLA-DM. HLA-DM stabilizes the open conformation of the MHCII binding groove...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Demharter S,Knapp B,Deane C,Minary P

    更新日期:2019-06-24 00:00:00

  • Fragment-Based Computational Method for Designing GPCR Ligands.

    abstract::G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, which is arguably the most important family of drug target. With the technology breakthroughs in X-ray crystallography and cryo-electron microscopy, more than 300 GPCR-ligand complex structures have been publicly reported since 2007,...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Li Y,Sun Y,Song Y,Dai D,Zhao Z,Zhang Q,Zhong W,Hu LA,Ma Y,Li X,Wang R

    更新日期:2020-09-28 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Hu G,Kuang G,Xiao W,Li W,Liu G,Tang Y

    更新日期:2012-05-25 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Brown WM,Sasson A,Bellew DR,Hunsaker LA,Martin S,Leitao A,Deck LM,Vander Jagt DL,Oprea TI

    更新日期:2008-08-01 00:00:00

  • Facile Solutions to the Problems Associated with Chemical Information and Mathematical Symbolism While Using Machine Translation Tools.

    abstract::Advances in computer-aided translation technology have made tremendous progress in accuracy in the past few years. Chemical Abstracts Service of the American Chemical Society summarizes scientific works from more than 50 languages and allows the users to search papers in nine selected languages. Currently, only the ab...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Wahab MF,Zulfiqar S,Sarwar MI,Lieberwirth I

    更新日期:2020-07-27 00:00:00

  • Novel inhibitors of human histone deacetylase (HDAC) identified by QSAR modeling of known inhibitors, virtual screening, and experimental validation.

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Tang H,Wang XS,Huang XP,Roth BL,Butler KV,Kozikowski AP,Jung M,Tropsha A

    更新日期:2009-02-01 00:00:00

  • Force Field Benchmark of Amino Acids. 2. Partition Coefficients between Water and Organic Solvents.

    abstract::The partitioning of amino acids between water and apolar environments is of vital importance in protein function and drug delivery. Here we present an extensive benchmark for octanol/water (log Poct), chloroform/water (log Pclf), and cyclohexane/water (log Pchx) partition coefficients of neutral amino acid side chain ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Zhang H,Jiang Y,Cui Z,Yin C

    更新日期:2018-08-27 00:00:00

  • Visualization of Solar Cell Library Space by Dimensionality Reduction Methods.

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Kaspi O,Yosipof A,Senderowitz H

    更新日期:2018-12-24 00:00:00

  • Drug effect prediction by polypharmacology-based interaction profiling.

    abstract::Most drugs exert their effects via multitarget interactions, as hypothesized by polypharmacology. While these multitarget interactions are responsible for the clinical effect profiles of drugs, current methods have failed to uncover the complex relationships between them. Here, we introduce an approach which is able t...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Simon Z,Peragovics A,Vigh-Smeller M,Csukly G,Tombor L,Yang Z,Zahoránszky-Kohalmi G,Végner L,Jelinek B,Hári P,Hetényi C,Bitter I,Czobor P,Málnási-Csizmadia A

    更新日期:2012-01-23 00:00:00

  • Consensus QSAR models: do the benefits outweigh the complexity?

    abstract::This study has assessed the use of consensus regression, as compared to single multiple linear regression, models for the development of quantitative structure-activity relationships (QSARs). To provide a comparison, four data sets of varying size and complexity were analyzed: silastic membrane flux, toxicity of pheno...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Hewitt M,Cronin MT,Madden JC,Rowe PH,Johnson C,Obi A,Enoch SJ

    更新日期:2007-07-01 00:00:00

  • Exploration of the accessible chemical space of acyclic alkanes.

    abstract::Saturated acyclic alkanes show steric strain if they are highly branched and, in extreme cases, fall apart rapidly at room temperature. Consequently, attempts to count the number of isomeric forms for a given molecular formula that neglect this physical consideration will inevitably overestimate the size of the availa...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Paton RS,Goodman JM

    更新日期:2007-11-01 00:00:00

  • Spatial sign preprocessing: a simple way to impart moderate robustness to multivariate estimators.

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Serneels S,De Nolf E,Van Espen PJ

    更新日期:2006-05-01 00:00:00

  • Learning To Predict Reaction Conditions: Relationships between Solvent, Molecular Structure, and Catalyst.

    abstract::Reaction databases provide a great deal of useful information to assist planning of experiments but do not provide any interpretation or chemical concepts to accompany this information. In this work, reactions are labeled with experimental conditions, and network analysis shows that consistencies within clusters of da...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Walker E,Kammeraad J,Goetz J,Robo MT,Tewari A,Zimmerman PM

    更新日期:2019-09-23 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Kearns FL,Robart C,Kemp MT,Vankayala SL,Chapin BM,Anslyn EV,Woodcock HL,Larkin JD

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  • Heuristics from Modeling of Spectral Overlap in Förster Resonance Energy Transfer (FRET).

    abstract::Among the photophysical parameters that underpin Förster resonance energy transfer (FRET), perhaps the least explored is the spectral overlap term ( J). While by definition J increases linearly with acceptor molar absorption coefficient (ε(A) in M-1 cm-1), is proportional to wavelength (λ4), and depends on the degree ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Qi Q,Taniguchi M,Lindsey JS

    更新日期:2019-02-25 00:00:00

  • Evaluation of Generalized Born Models for Large Scale Affinity Prediction of Cyclodextrin Host-Guest Complexes.

    abstract::Binding affinity prediction with implicit solvent models remains a challenge in virtual screening for drug discovery. In order to assess the predictive power of implicit solvent models in docking techniques with Amber scoring, three generalized Born models (GBHCT, GBOBCI, and GBOBCII) available in Dock 6.7 were utiliz...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Zhang H,Yin C,Yan H,van der Spoel D

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  • Assessment of the Cruzain Cysteine Protease Reversible and Irreversible Covalent Inhibition Mechanism.

    abstract::Reversible and irreversible covalent ligands are advanced cysteine protease inhibitors in the drug development pipeline. K777 is an irreversible inhibitor of cruzain, a necessary enzyme for the survival of the Trypanosoma cruzi (T. cruzi) parasite, the causative agent of Chagas disease. Despite their importance, irrev...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Silva JRA,Cianni L,Araujo D,Batista PHJ,de Vita D,Rosini F,Leitão A,Lameira J,Montanari CA

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  • Cross-docking of inhibitors into CDK2 structures. 2.

    abstract::In the preceding paper (Duca, J. S.; Madison, V. S.; Voigt, J. H. J. Chem. Inf. Model. 2008, 48, 659-668), the accuracy of docking and affinity predictions of the Gold and Glide programs were investigated using single protein conformations spanning 150 CDK2/inhibitor crystallographic complexes. High docking accuracy w...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Voigt JH,Elkin C,Madison VS,Duca JS

    更新日期:2008-03-01 00:00:00

  • Potent Human Telomerase Inhibitors: Molecular Dynamic Simulations, Multiple Pharmacophore-Based Virtual Screening, and Biochemical Assays.

    abstract::Telomere maintenance is a universal cancer hallmark, and small molecules that disrupt telomere maintenance generally have anticancer properties. Since the vast majority of cancer cells utilize telomerase activity for telomere maintenance, the enzyme has been considered as an anticancer drug target. Recently, rational ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Shirgahi Talari F,Bagherzadeh K,Golestanian S,Jarstfer M,Amanlou M

    更新日期:2015-12-28 00:00:00

  • Similarity perception of reactions catalyzed by oxidoreductases and hydrolases using different classification methods.

    abstract::In this work, the perception of similarity of reactions catalyzed by hydrolases and oxidoreductases on the basis of the overall breaking and making of bonds of reactions is investigated. Six physicochemical properties for the reacting bond in the substrate of each enzymatic reaction were calculated to describe the cha...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Hu X,Yan A,Tan T,Sacher O,Gasteiger J

    更新日期:2010-06-28 00:00:00

  • In silico prediction of aqueous solubility: the solubility challenge.

    abstract::The dissolution of a chemical into water is a process fundamental to both chemistry and biology. The persistence of a chemical within the environment and the effects of a chemical within the body are dependent primarily upon aqueous solubility. With the well-documented limitations hindering the accurate experimental d...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Hewitt M,Cronin MT,Enoch SJ,Madden JC,Roberts DW,Dearden JC

    更新日期:2009-11-01 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Koes DR,Camacho CJ

    更新日期:2011-06-27 00:00:00

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    abstract::A generic chemical transformation may often be achieved under various synthetic conditions. However, for any specific reagents, only one or a few among the reported synthetic protocols may be successful. For example, Michael β-addition reactions may proceed under different choices of solvent (e.g., hydrophobic, aproti...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Marcou G,Aires de Sousa J,Latino DA,de Luca A,Horvath D,Rietsch V,Varnek A

    更新日期:2015-02-23 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Zhou R,Xie Y,Hu H,Hu G,Patel VS,Zhang J,Yu K,Huang Y,Jiang H,Liang Z,Zheng YG,Luo C

    更新日期:2015-12-28 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 评论,信件


    authors: Saiakhov RD,Klopman G

    更新日期:2010-09-27 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Huang N,Kalyanaraman C,Irwin JJ,Jacobson MP

    更新日期:2006-01-01 00:00:00

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    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Bergant Loboda K,Janežič M,Štampar M,Žegura B,Filipič M,Perdih A

    更新日期:2020-07-27 00:00:00