Effects of Ligand Environment in Zr(IV) Assisted Peptide Hydrolysis.


:In this DFT study, activities of 11 different N2O4, N2O3, and NO2 core containing Zr(IV) complexes, 4,13-diaza-18-crown-6 (I'N2O4), 1,4,10-trioxa-7,13-diazacyclopentadecane (I'N2O3), and 2-(2-methoxy)ethanol (I'NO2), respectively, and their analogues in peptide hydrolysis have been investigated. Based on the experimental information, these molecules were created by altering protonation states (singly protonated, doubly protonated, or doubly deprotonated) and number of their ligands. The energetics of the I'N2O4, and I'NO2 and their analogues predicted that both stepwise and concerted mechanisms occurred either with similar barriers, or the latter was more favorable than the former. They also showed that the doubly deprotonated form hydrolyzed the peptide bond with substantially lower barriers than the barriers for other protonation states. For NO2 core possessing complexes, Zr-(NO2)(OHH)(H2O/OH)n for n = 1-3, the hydroxyl group containing molecules were found to be more reactive than their water ligand possessing counterparts. The barriers for these complexes reduced with an increase in the coordination number (6-8) of the Zr(IV) ion. Among all 11 molecules, the NO2 core possessing and two hydroxyl group containing I'DNO2-2H complex was found to be the most reactive complex with a barrier of 28.9 kcal/mol. Furthermore, barriers of 27.5, 28.9, and 32.0 kcal/mol for hydrolysis of Gly-Glu (negative), Gly-Gly (neutral), and Gly-Lys (positive) substrates, respectively, by this complex were in agreement with experiments. The activities of these complexes were explained in terms of basicity of their ligand environment and nucleophilicity of the Zr(IV) center using metal-ligand distances, charge on the metal ion, and the metal-nucleophile distance as parameters. These results provide a deeper understanding of the functioning of these complexes and will help design Zr(IV)-based synthetic metallopeptidases.


J Chem Inf Model


Zhang T,Sharma G,Paul TJ,Hoffmann Z,Prabhakar R




Has Abstract


2017-05-22 00:00:00












  • Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a.

    abstract::Peptides that bind to ion channels have attracted much interest as potential lead molecules for the development of new drugs and insecticides. However, the structure determination of large peptide-channel complexes using experimental methods is challenging. Thus structural models are often derived from combining exper...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Deplazes E,Davies J,Bonvin AM,King GF,Mark AE

    更新日期:2016-01-25 00:00:00

  • Time-Domain Analysis of Molecular Dynamics Trajectories Using Deep Neural Networks: Application to Activity Ranking of Tankyrase Inhibitors.

    abstract::Molecular dynamics simulations provide valuable insights into the behavior of molecular systems. Extending the recent trend of using machine learning techniques to predict physicochemical properties from molecular dynamics data, we propose to consider the trajectories as multidimensional time series represented by 2D ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Berishvili VP,Perkin VO,Voronkov AE,Radchenko EV,Syed R,Venkata Ramana Reddy C,Pillay V,Kumar P,Choonara YE,Kamal A,Palyulin VA

    更新日期:2019-08-26 00:00:00

  • Synergistic use of compound properties and docking scores in neural network modeling of CYP2D6 binding: predicting affinity and conformational sampling.

    abstract::Cytochrome P450 2D6 (CYP2D6) is used to develop an approach for predicting affinity and relevant binding conformation(s) for highly flexible binding sites. The approach combines the use of docking scores and compound properties as attributes in building a neural network (NN) model. It begins by identifying segments of...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Bazeley PS,Prithivi S,Struble CA,Povinelli RJ,Sem DS

    更新日期:2006-11-01 00:00:00

  • Identification of ligand templates using local structure alignment for structure-based drug design.

    abstract::With a rapid increase in the number of high-resolution protein-ligand structures, the known protein-ligand structures can be used to gain insight into ligand-binding modes in a target protein. On the basis of the fact that the structurally similar binding sites share information about their ligands, we have developed ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Lee HS,Im W

    更新日期:2012-10-22 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

  • Factors affecting d-block metal-ligand bond lengths: toward an automated library of molecular geometry for metal complexes.

    abstract::Metal-ligand (M-L) bond lengths for a range of ligands (carboxylates, chlorides, pyridines, water, tertiary phosphines, and alkenes) and a variety of metals have been retrieved from the Cambridge Structural Database, CSD. Analysis of the factors which affect M-L bond lengths (for example, ligand coordination mode, oxi...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Harris SE,Orpen AG,Bruno IJ,Taylor R

    更新日期:2005-11-01 00:00:00

  • Free energy calculations give insight into the stereoselective hydroxylation of α-ionones by engineered cytochrome P450 BM3 mutants.

    abstract::Previously, stereoselective hydroxylation of α-ionone by Cytochrome P450 BM3 mutants M01 A82W and M11 L437N was observed. While both mutants hydroxylate α-ionone in a regioselective manner at the C3 position, M01 A82W catalyzes formation of trans-3-OH-α-ionone products whereas M11 L437N exhibits opposite stereoselecti...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: de Beer SB,Venkataraman H,Geerke DP,Oostenbrink C,Vermeulen NP

    更新日期:2012-08-27 00:00:00

  • Delineation of agonist binding to the human histamine H4 receptor using mutational analysis, homology modeling, and ab initio calculations.

    abstract::A three-dimensional homology model of the human histamine H 4 receptor was developed to investigate the binding mode of a series of structurally diverse H 4-agonists, i.e. histamine, clozapine, and the recently described selective, nonimidazole agonist VUF 8430. Mutagenesis studies and docking of these ligands in a rh...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Jongejan A,Lim HD,Smits RA,de Esch IJ,Haaksma E,Leurs R

    更新日期:2008-07-01 00:00:00

  • Protein-protein binding site prediction by local structural alignment.

    abstract::Generalization of an earlier algorithm has led to the development of new local structural alignment algorithms for prediction of protein-protein binding sites. The algorithms use maximum cliques on protein graphs to define structurally similar protein regions. The search for structural neighbors in the new algorithms ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Carl N,Konc J,Vehar B,Janezic D

    更新日期:2010-10-25 00:00:00

  • Assessing the Protective Activity of a Recently Discovered Phenolic Compound against Oxidative Stress Using Computational Chemistry.

    abstract::The protection exerted by 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA), a phenolic compound recently isolated from the Pacific oyster, against oxidative stress (OS) is investigated using the density functional theory. Our results indicate that DHMBA is an outstanding peroxyl radical scavenger, being about 15 times an...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Villuendas-Rey Y,Alvarez-Idaboy JR,Galano A

    更新日期:2015-12-28 00:00:00

  • Parameterization and conformational sampling effects in pharmacophore multiplet searching.

    abstract::Pharmacophore patterns in ligands can be effectively characterized in terms of their constituent pharmacophore multiplets. Bitsets (fingerprints) encoding which particular multiplets are found in a given ligand have been and continue to be used as molecular descriptors in a range of molecular modeling applications, fr...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Fox PC,Wolohan PR,Abrahamian E,Clark RD

    更新日期:2008-12-01 00:00:00

  • Transplant-insert-constrain-relax-assemble (TICRA): protein-ligand complex structure modeling and application to kinases.

    abstract::We introduce TICRA (transplant-insert-constrain-relax-assemble), a method for modeling the structure of unknown protein-ligand complexes using the X-ray crystal structures of homologous proteins and ligands with known activity. We present results from modeling the structures of protein kinase-inhibitor complexes using...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Meshkat S,Klon AE,Zou J,Wiseman JS,Konteatis Z

    更新日期:2011-01-24 00:00:00

  • First Multitarget Chemo-Bioinformatic Model To Enable the Discovery of Antibacterial Peptides against Multiple Gram-Positive Pathogens.

    abstract::Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives to fight against the diverse infections caused by different pathogenic microorganisms. In this context, theoretical approaches in bioinformatics have paved the way toward the creation of several in silico models capable of predicting anti...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Speck-Planche A,Kleandrova VV,Ruso JM,Cordeiro MN

    更新日期:2016-03-28 00:00:00

  • Computational fragment-based approach at PDB scale by protein local similarity.

    abstract::The large volume of protein-ligand structures now available enables innovative and efficient protocols in computational FBDD (Fragment-Based Drug Design) to be proposed based on experimental data. In this work, we build a database of MED-Portions, where a MED-Portion is a new structural object encoding protein-fragmen...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Moriaud F,Doppelt-Azeroual O,Martin L,Oguievetskaia K,Koch K,Vorotyntsev A,Adcock SA,Delfaud F

    更新日期:2009-02-01 00:00:00

  • Heteroaromatic π-stacking energy landscapes.

    abstract::In this study we investigate π-stacking interactions of a variety of aromatic heterocycles with benzene using dispersion corrected density functional theory. We calculate extensive potential energy surfaces for parallel-displaced interaction geometries. We find that dispersion contributes significantly to the interact...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Huber RG,Margreiter MA,Fuchs JE,von Grafenstein S,Tautermann CS,Liedl KR,Fox T

    更新日期:2014-05-27 00:00:00

  • The valence state combination model: a generic framework for handling tautomers and protonation states.

    abstract::The consistent handling of molecules is probably the most basic and important requirement in the field of cheminformatics. Reliable results can only be obtained if the underlying calculations are independent of the specific way molecules are represented in the input data. However, ensuring consistency is a complex tas...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Urbaczek S,Kolodzik A,Rarey M

    更新日期:2014-03-24 00:00:00

  • Identifying promising compounds in drug discovery: genetic algorithms and some new statistical techniques.

    abstract::Throughout the drug discovery process, discovery teams are compelled to use statistics for making decisions using data from a variety of inputs. For instance, teams are asked to prioritize compounds for subsequent stages of the drug discovery process, given results from multiple screens. To assist in the prioritizatio...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Mandal A,Johnson K,Wu CF,Bornemeier D

    更新日期:2007-05-01 00:00:00

  • Binding Residence Time through Scaled Molecular Dynamics: A Prospective Application to hDAAO Inhibitors.

    abstract::Traditionally, a drug potency is expressed in terms of thermodynamic quantities, mostly Kd, and empirical IC50 values. Although binding affinity as an estimate of drug activity remains relevant, it is increasingly clear that it is also important to include (un)binding kinetic parameters in the characterization of pote...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Bernetti M,Rosini E,Mollica L,Masetti M,Pollegioni L,Recanatini M,Cavalli A

    更新日期:2018-11-26 00:00:00

  • Allosteric Modulation of Human Hsp90α Conformational Dynamics.

    abstract::Central to Hsp90's biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90's regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Penkler DL,Atilgan C,Tastan Bishop Ö

    更新日期:2018-02-26 00:00:00

  • Multiview Joint Learning-Based Method for Identifying Small-Molecule-Associated MiRNAs by Integrating Pharmacological, Genomics, and Network Knowledge.

    abstract::The emergence of a large amount of pharmacological, genomic, and network knowledge data provides new challenges and opportunities for drug discovery and development. Identification of real small-molecule drug (SM)-miRNA associations is not only important in the development of effective drug repositioning but also cruc...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Shen C,Luo J,Lai Z,Ding P

    更新日期:2020-08-24 00:00:00

  • Protein Solvent Shell Structure Provides Rapid Analysis of Hydration Dynamics.

    abstract::The solvation layer surrounding a protein is clearly an intrinsic part of protein structure-dynamics-function, and our understanding of how the hydration dynamics influences protein function is emerging. We have recently reported simulations indicating a correlation between regional hydration dynamics and the structur...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Dahanayake JN,Shahryari E,Roberts KM,Heikes ME,Kasireddy C,Mitchell-Koch KR

    更新日期:2019-05-28 00:00:00

  • Prediction of pH-dependent aqueous solubility of druglike molecules.

    abstract::In the present work, the Henderson-Hasselbalch (HH) equation has been employed for the development of a tool for the prediction of pH-dependent aqueous solubility of drugs and drug candidates. A new prediction method for the intrinsic solubility was developed, based on artificial neural networks that have been trained...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Hansen NT,Kouskoumvekaki I,Jørgensen FS,Brunak S,Jónsdóttir SO

    更新日期:2006-11-01 00:00:00

  • Combining 3-D quantitative structure-activity relationship with ligand based and structure based alignment procedures for in silico screening of new hepatitis C virus NS5B polymerase inhibitors.

    abstract::The viral NS5B RNA-dependent RNA-polymerase (RdRp) is one of the best-studied and promising targets for the development of novel therapeutics against hepatitis C virus (HCV). Allosteric inhibition of this enzyme has emerged as a viable strategy toward blocking replication of viral RNA in cell based systems. Herein, we...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Musmuca I,Caroli A,Mai A,Kaushik-Basu N,Arora P,Ragno R

    更新日期:2010-04-26 00:00:00

  • Structure-based discovery of novel non-nucleosidic DNA alkyltransferase inhibitors: virtual screening and in vitro and in vivo activities.

    abstract::The human DNA-repair O (6)-alkylguanine DNA alkyltransferase (MGMT or hAGT) protein protects DNA from environmental alkylating agents and also plays an important role in tumor resistance to chemotherapy treatment. Available inhibitors, based on pseudosubstrate analogs, have been shown to induce substantial bone marrow...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Ruiz FM,Gil-Redondo R,Morreale A,Ortiz AR,Fábrega C,Bravo J

    更新日期:2008-04-01 00:00:00

  • Baseline Model for Predicting Protein-Ligand Unbinding Kinetics through Machine Learning.

    abstract::Derivation of structure-kinetics relationships can help rational design and development of new small-molecule drug candidates with desired residence times. Efforts are now being directed toward the development of efficient computational methods. Currently, there is a lack of solid, high-throughput binding kinetics pre...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Amangeldiuly N,Karlov D,Fedorov MV

    更新日期:2020-12-28 00:00:00

  • Computational evidence for the role of Arabidopsis thaliana UVR8 as UV-B photoreceptor and identification of its chromophore amino acids.

    abstract::A homology model of the Arabidopsis thaliana UV resistance locus 8 (UVR8) protein is presented herein, showing a seven-bladed β-propeller conformation similar to the globular structure of RCC1. The UVR8 amino acid sequence contains a very high amount of conserved tryptophans, and the homology model shows that seven of...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Wu M,Grahn E,Eriksson LA,Strid A

    更新日期:2011-06-27 00:00:00

  • Heterogeneous Dielectric Implicit Membrane Model for the Calculation of MMPBSA Binding Free Energies.

    abstract::Membrane-bound protein receptors are a primary biological drug target, but the computational analysis of membrane proteins has been limited. In order to improve molecular mechanics Poisson-Boltzmann surface area (MMPBSA) binding free energy calculations for membrane protein-ligand systems, we have optimized a new hete...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Greene D,Qi R,Nguyen R,Qiu T,Luo R

    更新日期:2019-06-24 00:00:00

  • Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design.

    abstract::Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secr...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Poulsen A,Ho SY,Wang W,Alam J,Jeyaraj DA,Ang SH,Tan ES,Lin GR,Cheong VW,Ke Z,Lee MA,Keller TH

    更新日期:2015-07-27 00:00:00

  • Exploring Alternative Strategies for the Identification of Potent Compounds Using Support Vector Machine and Regression Modeling.

    abstract::Support vector regression (SVR) is a premier approach for the prediction of compound potency. Given the conceptual link between support vector machine (SVM) and SVR modeling, SVR is capable of accounting for continuous and discontinuous structure-activity relationships (SARs) in potency prediction, which further exten...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章


    authors: Miyao T,Funatsu K,Bajorath J

    更新日期:2019-03-25 00:00:00

  • 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

    更新日期:2020-03-23 00:00:00