Abstract：
:Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound showed an IC(50) in the micromolar range against dengue virus type 2.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Yennamalli R,Subbarao N,Kampmann T,McGeary RP,Young PR,Kobe Bdoi
10.1007/s10822-009-9263-6subject
Has Abstractpub_date
2009-06-01 00:00:00pages
333-41issue
6eissn
0920-654Xissn
1573-4951journal_volume
23pub_type
杂志文章abstract：:Multipoint interactions between synthetic and natural polymers provide a promising platform for many topical applications, including therapeutic blockage of virus-specific targets. Docking may become a useful tool for modelling of such interactions. However, the rigid docking cannot be correctly applied to synthetic p...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9621-7
更新日期：2012-12-01 00:00:00
abstract：:Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different cl...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-014-9757-8
更新日期：2014-07-01 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：:We have developed quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivi...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-005-4789-8
更新日期：2005-04-01 00:00:00
abstract：:The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contai...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0182-2
更新日期：2019-02-01 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：:A combined strategy based on the development of pharmacophore hypotheses and NMR approaches is reported for the identification of novel inhibitors of heparanase, a key enzyme involved in tumor metastasis through the remodeling of the subepithelial and subendothelial basement membranes, resulting in the dissemination o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9269-0
更新日期：2009-08-01 00:00:00
abstract：:Pamidronate, alendronate, APHBP and neridronate are a group of drugs, known as second-generation bisphosphonates (2G-BPs), commonly used in the treatment of bone-resorption disorders, and recently their use has been related to some collateral side effects. The therapeutic activity of 2G-BPs is related to the inhibitio...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0034-5
更新日期：2017-07-01 00:00:00
abstract：:Estimation of bioavailability and toxicity at the very beginning of the drug development process is one of the big challenges in drug discovery. Most of the processes involved in ADME are driven by rather unspecific interactions between drugs and biological macromolecules. Within the past decade, drug transport pumps ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1023828527638
更新日期：2002-11-01 00:00:00
abstract：:In this paper we describe our approaches to predict the binding mode of twenty BACE1 ligands as part of Grand Challenge 4 (GC4), organized by the Drug Design Data Resource. Calculations for all submissions (except for one, which used AutoDock4.2) were performed using AutoDock-GPU, the new GPU-accelerated version of Au...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00241-9
更新日期：2019-12-01 00:00:00
abstract：:In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-015-9880-1
更新日期：2015-12-01 00:00:00
abstract：:Fast Fourier transform (FFT) based approaches have been successful in application to modeling of relatively rigid protein-protein complexes. Recently, we have been able to adapt the FFT methodology to treatment of flexible protein-peptide interactions. Here, we report our latest attempt to expand the capabilities of t...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0069-7
更新日期：2018-01-01 00:00:00
abstract：:Crystal structures of the 1,4-dihydropyridine (1,4-DHP) calcium channel activators Bay K 8643 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-nitrophenyl)-pyridine-5-carboxy lat e], Bay O 8495 [methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(3-trifluoromethylphenyl)-pyridine-5- carboxylate], and Bay O 9507 [methyl 1,4-dihydr...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00129749
更新日期：1991-04-01 00:00:00
abstract：:Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to app...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0055-0
更新日期：2018-01-01 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：: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：:A method is suggested to calculate improved entropies within the MM/PBSA approach (molecular mechanics combined with Poisson-Boltzmann and surface area calculations) to estimate protein-ligand binding affinities. In the conventional approach, the protein is truncated outside ~8 A from the ligand. This system is freely...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-008-9238-z
更新日期：2009-02-01 00:00:00
abstract：:We have undertaken molecular dynamics simulations on the d(CGCAAAAAAGCG).d(CGCTTTTTTGCG) dodecamer in solution. In this study, we focus on aspects of conformation and dynamics, including the possibility of cross-strand hydrogen bonds. We compare our results with those from crystallography as well as infrared, Raman an...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00126748
更新日期：1994-06-01 00:00:00
abstract：:New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An ad...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007907728892
更新日期：1997-07-01 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：:Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00126666
更新日期：1991-08-01 00:00:00
abstract：:The Epstein-Barr Nuclear Antigen 1 (EBNA1) is a critical protein encoded by the Epstein-Barr Virus (EBV). During latent infection, EBNA1 is essential for DNA replication and transcription initiation of viral and cellular genes and is necessary to immortalize primary B-lymphocytes. Nonetheless, the concept of EBNA1 as ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-9899-y
更新日期：2016-04-01 00:00:00
abstract：:Two new continuum solvation models have been presented recently, and in this paper they are explained and reviewed in detail with further examples. Solvation Model 2 (AM1-SM2) is based on the Austin Model 1 and Solvation Model 3 (PM3-SM3) on the Parameterized Model 3 semiempirical Hamiltonian. In addition to the incor...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00126219
更新日期：1992-12-01 00:00:00
abstract：:The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00249-1
更新日期：2020-02-01 00:00:00
abstract：:Hydrogen bonds are the most specific, and therefore predictable of the intermolecular interactions involved in ligand-protein binding. Given the structure of a molecule, it is possible to estimate the positions at which complementary hydrogen-bonding atoms could be found. Crystal-survey data are used in the design of ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007900527102
更新日期：1997-05-01 00:00:00
abstract：:De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9473-6
更新日期：2011-10-01 00:00:00
abstract：:The previously proposed models for the recognition and activation of 5-HT and histamine-H2 receptors, which were employed to explain the antagonist activity of LSD at both of these receptors, as well as the selective antagonism for H2 receptors by SKF-10856 and 9,10-dihydro-LSD, are used herein to design a compound to...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124342
更新日期：1991-06-01 00:00:00
abstract：:Drug discovery is an expensive and time-consuming process. To make this process more efficient quantum chemistry methods can be employed. The electrophilicity index is one property that can be calculated by quantum chemistry methods, and if calculated correctly gives insight into the reactivity of covalent inhibitors....
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-020-00342-w
更新日期：2020-10-05 00:00:00
abstract：:To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-014-9709-3
更新日期：2014-04-01 00:00:00
