Abstract：
:Herein we investigate whether QM/MM could prove useful as a tool to study the often subtle binding phenomena found within pharmaceutical drug discovery programs. The goal of this investigation is to determine whether it is possible to employ high level QM/MM calculations to answer specific questions around a binding event in a cycle time that is aligned with medicinal chemistry synthesis. To this end QM/MM calculations have been performed on four protein kinase-ligand complexes using five different levels of theory, using standard hardware, in an effort to assess their utility. We conclude that the accuracy and turnaround time of such calculations mean they could prove valuable to (1) probe the subtle nature of the interactions within protein active sites, (2) facilitate the interpretation of poorly resolved electron density, and (3) study the impact of substituent changes on the binding conformation or in the assessment of alternate scaffolds. In practice, the successful application of such methods will be limited by the size of the system under investigation, the level of theory used, and whether there is a need for conformational sampling.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Gleeson MP,Gleeson Ddoi
10.1021/ci800419jsubject
Has Abstractpub_date
2009-03-01 00:00:00pages
670-7issue
3eissn
1549-9596issn
1549-960Xpii
10.1021/ci800419jjournal_volume
49pub_type
杂志文章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...
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journal_title：Journal of chemical information and modeling
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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
doi：10.1021/ci0500785
更新日期：2005-11-01 00:00:00
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journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
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journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/ci400245c
更新日期：2014-02-24 00:00:00
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
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更新日期：2009-06-01 00:00:00
abstract：:This paper presents an exploratory study of a novel method for flexible 3-D similarity searching based on autocorrelation vectors and smoothed bounded distance matrices. Although the new approach is unable to outperform an existing 2-D similarity searching in terms of enrichment factors, it is able to retrieve differe...
journal_title：Journal of chemical information and modeling
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更新日期：2006-03-01 00:00:00
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journal_title：Journal of chemical information and modeling
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doi：10.1021/ci400333x
更新日期：2013-10-28 00:00:00
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
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更新日期：2012-10-22 00:00:00
abstract：:The balance between structural stability and functional plasticity in proteins that share common three-dimensional folds is the key factor that drives protein evolvability. The ability to distinguish the parts of homologous proteins that underlie common structural organization patterns from the parts acting as regulat...
journal_title：Journal of chemical information and modeling
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更新日期：2017-04-24 00:00:00
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更新日期：2019-01-28 00:00:00
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更新日期：2007-05-01 00:00:00
abstract：:Characterizing the variability within an ensemble of protein structures is a common requirement in structural biology and bioinformatics. With the increasing number of protein structures becoming available, there is a need for new tools capable of automating the structural comparison of large ensemble of structures. W...
journal_title：Journal of chemical information and modeling
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更新日期：2013-09-23 00:00:00
abstract：:The recent article "Evaluation of pK(a) Estimation Methods on 211 Druglike Compounds" ( Manchester, J.; et al. J. Chem Inf. Model. 2010, 50, 565-571 ) reports poor results for the program Epik. Here, we highlight likely sources for the poor performance and describe work done to improve the performance. Running Epik in...
journal_title：Journal of chemical information and modeling
pub_type： 评论,杂志文章
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更新日期：2011-01-24 00:00:00
abstract：:Identifying drug-target interactions (DTIs) plays an important role in the field of drug discovery, drug side-effects, and drug repositioning. However, in vivo or biochemical experimental methods for identifying new DTIs are extremely expensive and time-consuming. Recently, in silico or various computational methods h...
journal_title：Journal of chemical information and modeling
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doi：10.1021/acs.jcim.9b00408
更新日期：2019-07-22 00:00:00
abstract：:Functional diversity of the three-finger-protein domain (TFPD) had been acquired via hypervariability of some sequence positions and extensive insertion/deletion of short AA-segments that caused multidimensional drift of several sequence attributes such as the overall (HI) and local hydrophobicity levels, the isoelect...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00322
更新日期：2015-09-28 00:00:00
abstract：:Cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphoshatase (cy-FBP/SBPase) is a potential enzymatic target for screening of novel inhibitors that can combat harmful algal blooms. In the present study, we targeted the substrate binding pocket of cy-FBP/SBPase. A series of novel hit compounds from the SPECs database w...
journal_title：Journal of chemical information and modeling
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更新日期：2014-03-24 00:00:00
abstract：:The Torsion Library contains hundreds of rules for small molecule conformations which have been derived from the Cambridge Structural Database (CSD) and are curated by molecular design experts. The torsion rules are encoded as SMARTS patterns and categorize rotatable bonds via a traffic light coloring scheme. We have ...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
doi：10.1021/acs.jcim.5b00522
更新日期：2016-01-25 00:00:00
abstract：:This study examines the dependence of molecular alignment accuracy on a variety of factors including the choice of molecular template, alignment method, conformational flexibility, and type of protein target. We used eight test systems for which X-ray data on 145 ligand-protein complexes were available. The use of X-r...
journal_title：Journal of chemical information and modeling
pub_type： 杂志文章
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更新日期：2006-09-01 00:00:00
