当前位置： SCI文献检索 > Journal of Chemical Information and Modeling期刊下所有文献 > Pushing the Limits of Computational Structure-Based Drug Design with a Cryo-EM Structure: The Ca2+ Channel α2δ-1 Subunit as a Test Case.

Pushing the Limits of Computational Structure-Based Drug Design with a Cryo-EM Structure: The Ca2+ Channel α2δ-1 Subunit as a Test Case.

Abstract：

:Cryo-electron microscopy (cryo-EM) is emerging as a real alternative for structural elucidation. In spite of this, very few cryo-EM structures have been described so far as successful platforms for in silico drug design. Gabapentin and pregabalin are some of the most successful drugs in the treatment of epilepsy and neuropathic pain. Although both are in clinical use and are known to exert their effects by binding to the regulatory α2δ subunit of voltage gated calcium channels, their binding modes have never been characterized. We describe here the successful use of an exhaustive protein-ligand sampling algorithm on the α2δ-1 subunit of the recently published cryo-EM structure, with the goal of characterizing the ligand entry path and binding mode for gabapentin, pregabalin, and several other amino acidic α2δ-1 ligands. Our studies indicate that (i) all simulated drugs explore the same path for accessing the occluded binding site on the interior of the α2δ-1 subunit; (ii) they all roughly occupy the same pocket; (iii) the plasticity of the binding site allows the accommodation of a variety of amino acidic modulators, driven by the flexible "capping loop" delineated by residues Tyr426-Val435 and the floppy nature of Arg217; (iv) the predicted binding modes are in line with previously available mutagenesis data, confirming Arg217 as key for binding, with Asp428 and Asp467 highlighted as additional anchoring points for all amino acidic drugs. The study is one of the first proofs that latest-generation cryo-EM structures combined with exhaustive computational methods can be exploited in early drug discovery.

journal_name

J Chem Inf Model

journal_title

Journal of chemical information and modeling

authors

Kotev M,Pascual R,Almansa C,Guallar V,Soliva R

doi

10.1021/acs.jcim.8b00347

subject

Has Abstract

pub_date

2018-08-27 00:00:00

pages

1707-1715

issue

8

eissn

1549-9596

issn

1549-960X

journal_volume

58

pub_type

杂志文章

相关文献

Journal of Chemical Information and Modeling文献大全
  • 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

    doi：10.1021/ci600556v

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

    更新日期：2007-05-01 00:00:00

  • Annotation of Allosteric Compounds to Enhance Bioactivity Modeling for Class A GPCRs.

    abstract：:Proteins often have both orthosteric and allosteric binding sites. Endogenous ligands, such as hormones and neurotransmitters, bind to the orthosteric site, while synthetic ligands may bind to orthosteric or allosteric sites, which has become a focal point in drug discovery. Usually, such allosteric modulators bind to...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.0c00695

    authors： Burggraaff L,van Veen A,Lam CC,van Vlijmen HWT,IJzerman AP,van Westen GJP

    更新日期：2020-10-26 00:00:00

  • RASA: a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules.

    abstract：:In this account, a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules, called RASA (Retrosynthesis-based Assessment of Synthetic Accessibility) is devised. RASA first constructs a synthesis tree for the target molecule based on retrosynthetic analysis; in thi...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci100216g

    authors： Huang Q,Li LL,Yang SY

    更新日期：2011-10-24 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

    doi：10.1021/acs.jcim.9b00135

    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

  • Instrument monitoring, data sharing, and archiving using Common Instrument Middleware Architecture (CIMA).

    abstract：:The Common Instrument Middleware Architecture (CIMA) aims at Grid-enabling a wide range of scientific instruments and sensors to enable easy access to and sharing and storage of data produced by these instruments and sensors. This paper describes the implementation of CIMA applied to the field of single-crystal X-ray ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci050368l

    authors： Bramley R,Chiu K,Devadithya T,Gupta N,Hart C,Huffman JC,Huffman K,Ma Y,McMullen DF

    更新日期：2006-05-01 00:00:00

  • Tuning Interaction Parameters of Thermoplastic Polyurethanes in a Binary Solvent To Achieve Precise Control over Microphase Separation.

    abstract：:Thermoplastic polyurethanes (TPUs) are designed using a large variety of basic building blocks but are only synthesized in a limited number of solvent systems. Understanding the behavior of the copolymers in a selected solvent system is of particular interest to tune the intricate balance of microphase separation/mixi...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.8b00781

    authors： Avaz Seven S,Oguz O,Menceloglu YZ,Atilgan C

    更新日期：2019-05-28 00:00:00

  • PiNN: A Python Library for Building Atomic Neural Networks of Molecules and Materials.

    abstract：:Atomic neural networks (ANNs) constitute a class of machine learning methods for predicting potential energy surfaces and physicochemical properties of molecules and materials. Despite many successes, developing interpretable ANN architectures and implementing existing ones efficiently are still challenging. This call...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b00994

    authors： Shao Y,Hellström M,Mitev PD,Knijff L,Zhang C

    更新日期：2020-03-23 00:00:00

  • What Does the Machine Learn? Knowledge Representations of Chemical Reactivity.

    abstract：:In a departure from conventional chemical approaches, data-driven models of chemical reactions have recently been shown to be statistically successful using machine learning. These models, however, are largely black box in character and have not provided the kind of chemical insights that historically advanced the fie...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b00721

    authors： Kammeraad JA,Goetz J,Walker EA,Tewari A,Zimmerman PM

    更新日期：2020-03-23 00:00:00

  • Identifying biologically active compound classes using phenotypic screening data and sampling statistics.

    abstract：:Scoring the activity of compounds in phenotypic high-throughput assays presents a unique challenge because of the limited resolution and inherent measurement error of these assays. Techniques that leverage the structural similarity of compounds within an assay can be used to improve the hit-recovery rate from screenin...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci050087d

    authors： Klekota J,Brauner E,Schreiber SL

    更新日期：2005-11-01 00:00:00

  • Structural insight into the unique binding properties of pyridylethanol(phenylethyl)amine inhibitor in human CYP51.

    abstract：:Sterol 14α-demethylase (CYP51) is the main drug target for the treatment of fungal infections. The discovery of new efficient fungal CYP51 inhibitors requires an understanding of the structural requirements for selectivity for the fungal over the human ortholog. In this study, a binding mode of the pyridylethanol(phen...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci500556k

    authors： Zelenko U,Hodošček M,Rozman D,Golič Grdadolnik S

    更新日期：2014-12-22 00:00:00

  • Assessing different classification methods for virtual screening.

    abstract：:How well do different classification methods perform in selecting the ligands of a protein target out of large compound collections not used to train the model? Support vector machines, random forest, artificial neural networks, k-nearest-neighbor classification with genetic-algorithm-optimized feature selection, tren...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci050519k

    authors： Plewczynski D,Spieser SA,Koch U

    更新日期：2006-05-01 00:00:00

  • Comparative analysis of binding energy of chymostatin with human cathepsin A and its homologous proteins by molecular orbital calculation.

    abstract：:Cathepsin A is a mammalian lysosomal enzyme that catalyzes the hydrolysis of the carboxy-terminal amino acids of polypeptides and also regulates beta-galactosidase and neuraminidase-1 activities through the formation of a multienzymic complex in lysosomes. Human cathepsin A (hCathA), yeast carboxypeptidase (CPY), and ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci060093p

    authors： Yoshida T,Lepp Z,Kadota Y,Satoh Y,Itoh K,Chuman H

    更新日期：2006-09-01 00:00:00

  • Ranking chemical structures for drug discovery: a new machine learning approach.

    abstract：:With chemical libraries increasingly containing millions of compounds or more, there is a fast-growing need for computational methods that can rank or prioritize compounds for screening. Machine learning methods have shown considerable promise for this task; indeed, classification methods such as support vector machin...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci9003865

    authors： Agarwal S,Dugar D,Sengupta S

    更新日期：2010-05-24 00:00:00

  • Automated extraction of information on chemical-P-glycoprotein interactions from the literature.

    abstract：:Knowledge of the interactions between drugs and transporters is important for drug discovery and development as well as for the evaluation of their clinical safety. We recently developed a text-mining system for the automatic extraction of information on chemical-CYP3A4 interactions from the literature. This system is...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci4003188

    authors： Yoshida S,Yamashita F,Ose A,Maeda K,Sugiyama Y,Hashida M

    更新日期：2013-10-28 00:00:00

  • Flux (2): comparison of molecular mutation and crossover operators for ligand-based de novo design.

    abstract：:We implemented a fragment-based de novo design algorithm for a population-based optimization of molecular structures. The concept is grounded on an evolution strategy with mutation and crossover operators for structure breeding. Molecular building blocks were obtained from the pseudo-retrosynthesis of a collection of ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci6005307

    authors： Fechner U,Schneider G

    更新日期：2007-03-01 00:00:00

  • Virtual drug screen schema based on multiview similarity integration and ranking aggregation.

    abstract：:The current drug virtual screen (VS) methods mainly include two categories. i.e., ligand/target structure-based virtual screen and that, utilizing protein-ligand interaction fingerprint information based on the large number of complex structures. Since the former one focuses on the one-side information while the later...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci200481c

    authors： Kang H,Sheng Z,Zhu R,Huang Q,Liu Q,Cao Z

    更新日期：2012-03-26 00:00:00

  • Structural protein-ligand interaction fingerprints (SPLIF) for structure-based virtual screening: method and benchmark study.

    abstract：:Accurate and affordable assessment of ligand-protein affinity for structure-based virtual screening (SB-VS) is a standing challenge. Hence, empirical postdocking filters making use of various types of structure-activity information may prove useful. Here, we introduce one such filter based upon three-dimensional struc...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci500319f

    authors： Da C,Kireev D

    更新日期：2014-09-22 00:00:00

  • CoNTub v2.0--algorithms for constructing C3-symmetric models of three-nanotube junctions.

    abstract：:Here, a method is described for easily building three-carbon nanotube junctions. It allows the geometry to be found and bond connectivity of C(3) symmetric nanotube junctions to be established. Such junctions may present a variable degree of pyramidalization and are composed of three identical carbon nanotubes with ar...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci200056p

    authors： Melchor S,Martin-Martinez FJ,Dobado JA

    更新日期：2011-06-27 00:00:00

  • A probabilistic approach to classifying metabolic stability.

    abstract：:Metabolic stability is an important property of drug molecules that should-optimally-be taken into account early on in the drug design process. Along with numerous medium- or high-throughput assays being implemented in early drug discovery, a prediction tool for this property could be of high value. However, metabolic...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci700142c

    authors： Schwaighofer A,Schroeter T,Mika S,Hansen K,Ter Laak A,Lienau P,Reichel A,Heinrich N,Müller KR

    更新日期：2008-04-01 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

    doi：10.1021/acs.jcim.9b00363

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

    更新日期：2019-06-24 00:00:00

  • Estimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations.

    abstract：:Group 1 metabotropic glutamate receptors (mGluR) are G-protein coupled receptors with a large bilobate extracellular ligand binding region (LBR) that resembles a Venus fly trap. Closing of this LBR in the presence of a ligand is associated with the activation of the receptor. From conformational sampling of the LBR-li...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci400160x

    authors： Lakkaraju SK,Xue F,Faden AI,MacKerell AD Jr

    更新日期：2013-06-24 00:00:00

  • Retrospect and Prospect of Single Particle Cryo-Electron Microscopy: The Class of Integral Membrane Proteins as an Example.

    abstract：:A giant technological leap in the field of cryo-electron microscopy (cryo-EM) has assured the achievement of near-atomic resolution structures of biological macromolecules. As a recognition of this accomplishment, the Nobel Prize in Chemistry was awarded in 2017 to Jacques Dubochet, Joachim Frank, and Richard Henderso...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b01015

    authors： Akbar S,Mozumder S,Sengupta J

    更新日期：2020-05-26 00:00:00

  • Comparative Dynamics and Functional Mechanisms of the CYP17A1 Tunnels Regulated by Ligand Binding.

    abstract：:As an important member of cytochrome P450 (CYP) enzymes, CYP17A1 is a dual-function monooxygenase with a critical role in the synthesis of many human steroid hormones, making it an attractive therapeutic target. The emerging structural information about CYP17A1 and the growing number of inhibitors for these enzymes ca...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.0c00447

    authors： Xiao F,Song X,Tian P,Gan M,Verkhivker GM,Hu G

    更新日期：2020-07-27 00:00:00

  • FAME 3: Predicting the Sites of Metabolism in Synthetic Compounds and Natural Products for Phase 1 and Phase 2 Metabolic Enzymes.

    abstract：:In this work we present the third generation of FAst MEtabolizer (FAME 3), a collection of extra trees classifiers for the prediction of sites of metabolism (SoMs) in small molecules such as drugs, druglike compounds, natural products, agrochemicals, and cosmetics. FAME 3 was derived from the MetaQSAR database ( Pedre...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.9b00376

    authors： Šícho M,Stork C,Mazzolari A,de Bruyn Kops C,Pedretti A,Testa B,Vistoli G,Svozil D,Kirchmair J

    更新日期：2019-08-26 00:00:00

  • Molecular Dynamics Simulations of Membrane-Bound STIM1 to Investigate Conformational Changes during STIM1 Activation upon Calcium Release.

    abstract：:Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically, calcium levels are kept at less than 100 nM in the nucleus and cytosol, but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intr...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/acs.jcim.6b00475

    authors： Mukherjee S,Karolak A,Debant M,Buscaglia P,Renaudineau Y,Mignen O,Guida WC,Brooks WH

    更新日期：2017-02-27 00:00:00

  • Accurate prediction of adsorption energies on graphene, using a dispersion-corrected semiempirical method including solvation.

    abstract：:The accurate prediction of the adsorption energies of unsaturated molecules on graphene in the presence of water is essential for the design of molecules that can modify its properties and that can aid its processability. We here show that a semiempirical MO method corrected for dispersive interactions (PM6-DH2) can p...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci5003729

    authors： Vincent MA,Hillier IH

    更新日期：2014-08-25 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

    doi：10.1021/ci100256u

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

    更新日期：2011-01-24 00:00:00

  • Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures.

    abstract：:To discover non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that are effective against both wild-type (WT) virus and variants that encode the clinically troublesome Tyr181Cys (Y181C) RT mutation, virtual screening by docking was carried out using three RT structures and more than 2 million commercial...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci900068k

    authors： Nichols SE,Domaoal RA,Thakur VV,Tirado-Rives J,Anderson KS,Jorgensen WL

    更新日期：2009-05-01 00:00:00

  • Technique for energy decomposition in the study of "receptor-ligand" complexes.

    abstract：:A new methodology to describe the interactions in "receptor-ligand" complexes is presented. The methodology is based on a combination of the 3D/4D QSAR BiS/MC and CoCon algorithms. The first algorithm performs the restricted docking of compounds to receptor pockets. The second determines the relationships between the ...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci800405n

    authors： Potemkin VA,Pogrebnoy AA,Grishina MA

    更新日期：2009-06-01 00:00:00

  • Template CoMFA: the 3D-QSAR Grail?

    abstract：:Template CoMFA, a novel alignment methodology for training or test set structures in 3D-QSAR, is introduced. Its two most significant advantages are its complete automation and its ability to derive a single combined model from multiple structural series affecting a biological target. Its only two inputs are one or mo...

    journal_title：Journal of chemical information and modeling

    pub_type： 杂志文章

    doi：10.1021/ci400696v

    authors： Cramer RD,Wendt B

    更新日期：2014-02-24 00:00:00