Abstract:
:The bacterial ribosome is a major target of naturally occurring thiopeptides antibiotics. Studying thiopeptide (e.g. thiostrepton) binding to the GAR's 23S·L11 ribosomal subunit using docking methods is challenging. Regarding the target, the binding site is composed of a flexible protein-RNA nonbonded interface whose available crystal structure is of medium resolution. Regarding the ligands, the thiopeptides are chemically complex, flexible, and contain macrocycles. In this study we developed a combined MD-docking-MD workflow that allows us to study thiopeptide-23S·L11 binding. It is shown that docking thiostrepton-like ligands to an MD-refined receptor structure instead of the medium resolution crystal leads to better convergence to the native-like docking pose and a better reproduction of experimental binding affinities. By applying an energy decomposition analysis, we identify key structural binding elements within GAR's rRNA-protein binding site and within the ligand structures.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Wolf A,Schoof S,Baumann S,Arndt HD,Kirschner KNdoi
10.1007/s10822-014-9797-0subject
Has Abstractpub_date
2014-12-01 00:00:00pages
1205-15issue
12eissn
0920-654Xissn
1573-4951journal_volume
28pub_type
杂志文章abstract::The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challeng...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-9946-8
更新日期:2016-09-01 00:00:00
abstract::Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, c...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-011-9533-y
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abstract::When we build a predictive model of a drug property we rigorously assess its predictive accuracy, but we are rarely able to address the most important question, "How useful will the model be in making a decision in a practical context?" To answer this requires an understanding of the prior probability distribution ("t...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-010-9388-7
更新日期:2010-12-01 00:00:00
abstract::Electrostatic potential complementarity between ligands and their receptor sites is evaluated by the superposition of the electrostatic potential, generated by the receptor, onto the ligand potential over the ligand van der Waals surface. We would like to examine which structural factors generate this pattern of super...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00123665
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abstract::This paper tests the performance of a simple empirical scoring function on a set of candidate designs produced by a de novo design package. The scoring function calculates approximate ligand-receptor binding affinities given a putative binding geometry. To our knowledge this is the first substantial test of an empiric...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008040323669
更新日期:1998-09-01 00:00:00
abstract::Many commercially available software programs claim similar efficiency and accuracy as variable selection tools. Genetic algorithms are commonly used variable selection methods where most relevant variables can be differentiated from 'less important' variables using evolutionary computing techniques. However, differen...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-004-5322-1
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abstract::Modelling studies have been carried out on the phosphodiesterase (PDE) substrates, adenosine- and guanosine-3'5'-cyclic monophosphates, and on a number of non-specific and type III-specific phosphodiesterase inhibitors. These studies have assisted the understanding of PDE substrate differentiation and the design of po...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01676955
更新日期:1987-07-01 00:00:00
abstract::The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed th...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-0005-2
更新日期:2017-02-01 00:00:00
abstract::Computational techniques, such as Quantitative Structure-Property Relationship (QSPR) modeling, are very useful in predicting physicochemical properties of various chemicals. Building QSPR models requires calculating molecular descriptors and the proper choice of the geometry optimization method, which will be dedicat...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-9894-3
更新日期:2016-02-01 00:00:00
abstract::In this work, the antimalarial activity of two series of 20 and 7 synthetic 1,2,4-trioxanes and a set of 20 cyclic peroxy ketals are tested for correlation search by means of Molecular Quantum Similarity Measures (MQSM). QSAR models, dealing with different biological responses (IC90, IC50 and ED90) of the parasite Pla...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1015917510236
更新日期:2001-12-01 00:00:00
abstract::Accurate and well-curated experimental pKa data of organic acids and bases in both aqueous and non-aqueous media are invaluable in many areas of chemical research, including pharmaceutical, agrochemical, specialty chemical and property prediction research. In pharmaceutical research, pKa data are relevant in ligand de...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9764-9
更新日期:2014-10-01 00:00:00
abstract::The V2 vasopressin renal receptor (V2R), which controls antidiuresis in mammals, is a member of the large family of heptahelical transmembrane (7TM) G protein-coupled receptors (GPCRs). Using the automated GPCR modeling facility available via Internet (http:/(/)expasy.hcuge.ch/swissmod/SWISS-MODEL.+ ++html) for constr...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007969526447
更新日期:1998-05-01 00:00:00
abstract::In the 1960s, the kappa statistic was introduced for the estimation of chance agreement in inter- and intra-rater reliability studies. The kappa statistic was strongly pushed by the medical field where it could be successfully applied via analyzing diagnoses of identical patient groups. Kappa is well suited for classi...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9759-6
更新日期:2014-11-01 00:00:00
abstract::A method has been developed that allows one to drive a molecule to conformations of lowest energy given the starting conformation, the identity of the rotatable bonds and the step size. This method has proved useful in our hands in the drug design arena where it is frequently more important to get 'low-energy' conform...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00117278
更新日期:1995-02-01 00:00:00
abstract::RNA interference (RNAi) is a critical cellular pathway activated by double stranded RNA and regulates the gene expression of target mRNA. During RNAi, the 3' end of siRNA binds with the PAZ domain, followed by release and rebinding in a cyclic manner, which deemed essential for proper gene silencing. Recently, we prov...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-013-9665-3
更新日期:2013-07-01 00:00:00
abstract::Although auxins were the first type of plant hormone to be identified, little is known about the molecular mechanism of this important class of plant hormones. We present a classification of a set of about 50 compounds with measured auxin activities, according to their interaction properties. Four classes of compounds...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007973008558
更新日期:1998-01-01 00:00:00
abstract::Cheminformatics protocols have been developed and assessed that identify a small set of fragments which can represent the compounds in a chemical library for use in fragment-based ligand discovery. Six different methods have been implemented and tested on Input Libraries of compounds from three suppliers. The resultin...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-011-9461-x
更新日期:2011-07-01 00:00:00
abstract::Mycobacterium tuberculosis (Mtb) 16.3 kDa heat shock protein 16.3 (HSP16.3) is a latency-associated antigen that can be targeted for latent tuberculosis (TB) diagnostic and therapeutic development. We have previously developed human VH domain antibodies (dAbs; clone E3 and F1) specific against HSP16.3. In this work, w...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-019-00186-z
更新日期:2019-03-01 00:00:00
abstract::Evidenced by the three-rounds of G-protein coupled receptors (GPCR) Dock competitions, improving homology modeling methods of helical transmembrane proteins including the GPCRs, based on templates of low sequence identity, remains an eminent challenge. Current approaches addressing this challenge adopt the philosophy ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9823-2
更新日期:2015-05-01 00:00:00
abstract::The de novo design program Skelgen has been used to design inhibitor structures for four targets of pharmaceutical interest. The designed structures are compared to modeled binding modes of known inhibitors (i) visually and (ii) by means of a novel similarity measure considering the size and spatial proximity of the m...
journal_title:Journal of computer-aided molecular design
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更新日期:2002-07-01 00:00:00
abstract::The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters,...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008130001697
更新日期:2000-03-01 00:00:00
abstract::Glucokinase (GK) is involved in normal glucose homeostasis and therefore it is a valid target for drug design and discovery efforts. GK activators (GKAs) have excellent potential as treatments of hyperglycemia and diabetes. The combined recent interest in GKAs, together with docking limitations and shortages of dockin...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9740-4
更新日期:2014-05-01 00:00:00
abstract::Leishmania donovani dipeptidylcarboxypeptidsae (LdDCP), an angiotensin converting enzyme (ACE) related metallopeptidase has been identified and characterized as a putative drug target for antileishmanial chemotherapy. The kinetic parameters for LdDCP with substrate, Hip-His-Leu were determined as, Km, 4 mM and Vmax, 1...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-009-9315-y
更新日期:2010-01-01 00:00:00
abstract::The pKa is the standard measure used to describe the aqueous proton affinity of a compound, indicating the proton concentration (pH) at which two protonation states (e.g. A- and AH) have equal free energy. However, compounds can have additional protonation states (e.g. AH2+), and may assume multiple tautomeric forms, ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00280-7
更新日期:2020-05-01 00:00:00
abstract::The use of MP2 level quantum mechanical (QM) calculations on isolated heteroaromatic ring systems for the prediction of the tautomeric propensities of whole molecules in a crystalline environment was examined. A Polarisable Continuum Model was used in the calculations to account for environment effects on the tautomer...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-010-9345-5
更新日期:2010-06-01 00:00:00
abstract::In this paper a database of small frequently occurring molecular fragments is used for the determination of fragment bond lengths from the Cambridge Structural Database. A large number of bond types are described that have not been reported previously. ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00125946
更新日期:1992-08-01 00:00:00
abstract::Capacity ratio (log k') values, which are a measure of hydrophobicity, were calculated directly from the three-dimensional structures of 17 furans and 54 triazines using the comparative molecular field analysis approach. The H2O probe and the GRID force field, including hydrogen-bond potentials, yielded excellent corr...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00125172
更新日期:1995-08-01 00:00:00
abstract::Folate receptor α (FRα) is a cell surface, glycophosphatidylinositol-anchored protein which has focussed attention as a therapeutic target and as a marker for the diagnosis of cancer. It has a high affinity for the dietary supplemented folic acid (FOL), carrying out endocytic transport across the cell membrane and del...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9801-8
更新日期:2015-01-01 00:00:00
abstract::Chemical space networks (CSNs) have recently been introduced as an alternative to other coordinate-free and coordinate-based chemical space representations. In CSNs, nodes represent compounds and edges pairwise similarity relationships. In addition, nodes are annotated with compound property information such as biolog...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-015-9872-1
更新日期:2015-10-01 00:00:00
abstract::In this work the rigid-analogue approach has been used to obtain information on the active conformation(s) of the calcium antagonist verapamil. A series of semi-rigid analogues of verapamil were synthesized and their biological activities evaluated on guinea-pig heart and aorta. These molecules were analysed by means ...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00119863
更新日期:1994-04-01 00:00:00