Abstract：
:Molecular structures and functions of the majority of proteins across different species are yet to be identified. Much needed functional annotation of these gene products often benefits from the knowledge of protein-ligand interactions. Towards this goal, we developed eFindSite, an improved version of FINDSITE, designed to more efficiently identify ligand binding sites and residues using only weakly homologous templates. It employs a collection of effective algorithms, including highly sensitive meta-threading approaches, improved clustering techniques, advanced machine learning methods and reliable confidence estimation systems. Depending on the quality of target protein structures, eFindSite outperforms geometric pocket detection algorithms by 15-40 % in binding site detection and by 5-35 % in binding residue prediction. Moreover, compared to FINDSITE, it identifies 14 % more binding residues in the most difficult cases. When multiple putative binding pockets are identified, the ranking accuracy is 75-78 %, which can be further improved by 3-4 % by including auxiliary information on binding ligands extracted from biomedical literature. As a first across-genome application, we describe structure modeling and binding site prediction for the entire proteome of Escherichia coli. Carefully calibrated confidence estimates strongly indicate that highly reliable ligand binding predictions are made for the majority of gene products, thus eFindSite holds a significant promise for large-scale genome annotation and drug development projects. eFindSite is freely available to the academic community at http://www.brylinski.org/efindsite .
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Brylinski M,Feinstein WPdoi
10.1007/s10822-013-9663-5subject
Has Abstractpub_date
2013-06-01 00:00:00pages
551-67issue
6eissn
0920-654Xissn
1573-4951journal_volume
27pub_type
杂志文章abstract：:A major problem in modelling (biological) macromolecules is the search for low-energy conformations. The complexity of a conformational search problem increases exponentially with the number of degrees of freedom which means that a systematic search can only be performed for very small structures. Here we introduce a ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00129422
更新日期：1992-04-01 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：:Optimization in medicinal chemistry often involves designing replacements for a section of a molecule which aim to retain potency while improving other properties of the compound. In this study, we perform a retrospective analysis using a number of computational methods to identify active side chains amongst a pool of...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-020-00313-1
更新日期：2020-09-01 00:00:00
abstract：:The pharmacophoric concept plays an important role in ligand-based drug design methods to describe the similarity and diversity of molecules, and could also be exploited as a molecular representation scheme. A three-point pharmacophore method was used as a molecular representation perception. This procedure was implem...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9110-6
更新日期：2007-05-01 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 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：:Steric complementarity is a prerequisite for ligand-receptor recognition; this implies that drugs with a common receptor binding site should possess sterically similar binding surfaces. This principle is used as the basis for an automatic and unbiased method that superposes molecules. One molecule is rotated and trans...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124319
更新日期：1995-12-01 00:00:00
abstract：:As part of the fourth statistical assessment of modeling of proteins and ligands (sampl.eyesopen.com) prediction challenge, the strength of association of nine guests (1-9) binding to octa-acid host was determined by a combination of (1)H NMR and isothermal titration calorimetry. Association constants in sodium tetrab...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-013-9690-2
更新日期：2014-04-01 00:00:00
abstract：:The interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives (compound 1 (N, N-Dipropyl-1-(2-phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-1,2,3-triazole-4-methanamine) and 2 (1-(2-Phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-4-(morpholin-4-ylmethyl)-1H-1,2,3-triazole)) with H(+),K(+)-ATPase at diff...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-015-9886-8
更新日期：2016-01-01 00:00:00
abstract：:We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (str...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9569-7
更新日期：2012-04-01 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
更新日期：2012-06-01 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
abstract：:All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydra...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9527-9
更新日期：2012-05-01 00:00:00
abstract：:The growing number of protein-ligand complex structures, particularly the structures of proteins co-bound with different ligands, in the Protein Data Bank helps us tackle two major challenges in molecular docking studies: the protein flexibility and the scoring function. Here, we introduced a systematic strategy by us...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0038-1
更新日期：2017-08-01 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：: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：:Feature selection is commonly used as a preprocessing step to machine learning for improving learning performance, lowering computational complexity and facilitating model interpretation. This paper proposes the application of boosting feature selection to improve the classification performance of standard feature sel...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0171-5
更新日期：2018-11-01 00:00:00
abstract：:ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are report...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0052-3
更新日期：2017-10-01 00:00:00
abstract：:In the present work we have modeled the Michaelis complex of the cyclic-Adenosine Monophosphate Dependent (cAMD) Protein Kinase A (PKA) with Mg(2)ATP and the heptapeptide substrate Kemptide by classical molecular dynamics. The chosen synthetic substrate is relevant for its high efficiency and small size, and it has no...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9143-x
更新日期：2007-10-01 00:00:00
abstract：:During the last few years, we have developed a docking protocol involving two steps: (i) the choice of the most appropriate docking software and parameters for the system of interest using structural and functional information available in public databases (PDB, ChEMBL, PubChem Assay, BindingDB, etc.); (ii) the dockin...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0161-7
更新日期：2019-01-01 00:00:00
abstract：:The Ligand Design (LUDI) approach has been used in order to design leucine aminopeptidase inhibitors, predict their activity and analyze their interactions with the enzyme. The investigation was based on the crystal structure of bovine lens leucine aminopeptidase (LAP) complexed with its inhibitor--the phosphonic acid...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008189716955
更新日期：2000-08-01 00:00:00
abstract：:Literature UV absorption intensities at 260 nm and 25 degrees C in water of a diverse set of 805 organic compounds when analyzed by CODESSA Pro software using an initial pool of 800 + descriptors provide a significant QSPR correlation (R (2) = 0.692). Concurrently, a neural networks approach was used to develop a corr...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9118-y
更新日期：2007-07-01 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：:In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters hig...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0114-1
更新日期：2018-05-01 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：:Manifold representations of rotational/translational motion and conformational space of a ligand were previously shown to be effective for local energy optimization. In this paper we report the development of the Monte-Carlo energy minimization approach (MCM), which uses the same manifold representation. The approach ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0176-0
更新日期：2019-01-01 00:00:00
abstract：:It is essential, in order to minimise expensive drug failures due to toxicity being found in late development or even in clinical trials, to determine potential toxicity problems as early as possible. In view of the large libraries of compounds now being handled by combinatorial chemistry and high-throughput screening...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章,评审
doi：10.1023/a:1025361621494
更新日期：2003-02-01 00:00:00
abstract：:This paper describes several case studies concerning protein function inference from its structure using our novel approach described in the accompanying paper. This approach employs family-specific motifs, i.e. three-dimensional amino acid packing patterns that are statistically prevalent within a protein family. For...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9277-0
更新日期：2009-11-01 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：: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
