Abstract:
:Arachidonic acid is an essential fatty acid in cells, acting as a key inflammatory intermediate in inflammatory reactions. In cardiac tissues, CYP2J2 can adopt arachidonic acid as a major substrate to produce epoxyeicosatrienoic acids (EETs), which can protect endothelial cells from ischemic or hypoxic injuries and have been implicated in the pathogenesis of coronary artery disease and hypertension. However, some CYP2J2 polymorphisms, i.e., T143A and N404Y, significantly reduce the metabolism of arachidonic acid. Lacking experimental structural data for CYP2J2, the detailed mechanism for the mutation-induced dysfunction in the metabolism of arachidonic acid is still unknown. In the current study, three-dimensional structural models of the wild-type CYP2J2 and two mutants (T143A and N404Y) were constructed by a coordinate reconstruction approach and ab initio modeling using CYP2R1 as a template. The structural analysis of the computational models showed that the wild-type CYP2J2 exhibited a typical CYP fold with 12 alpha-helices and three beta-sheets on one side and with the heme group buried deeply inside the core. Due to the small and hydrophobic side-chain, T143A mutation could destabilize the C helix, further placing the water access channel in a closed state to prevent the escape of the produced water molecules during the catalytic processes. N404Y mutation could reposition the side-chain of Leu(378), making it no longer form a hydrogen bond with the carboxyl group of arachidonic acid. However, this hydrogen bond was essential for substrate recognition and positioning in a correct orientation.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Cong S,Ma XT,Li YX,Wang JFdoi
10.1021/ci400003psubject
Has Abstractpub_date
2013-06-24 00:00:00pages
1350-7issue
6eissn
1549-9596issn
1549-960Xjournal_volume
53pub_type
杂志文章abstract::An accurate scoring function is expected to correctly select the most stable structure from a set of pose candidates. One can hypothesize that a scoring function's ability to identify the most stable structure might be improved by emphasizing the most relevant atom pairwise interactions. However, it is hard to evaluat...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00356
更新日期:2019-07-22 00:00:00
abstract::The urgent need for new treatments for the chronic lung disease idiopathic pulmonary fibrosis (IPF) motivates research into antagonists of the RGD binding integrin αvβ6, a protein linked to the initiation and progression of the disease. Molecular dynamics (MD) simulations of αvβ6 in complex with its natural ligand, pr...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00254
更新日期:2020-11-23 00:00:00
abstract::Advances in computer-aided translation technology have made tremendous progress in accuracy in the past few years. Chemical Abstracts Service of the American Chemical Society summarizes scientific works from more than 50 languages and allows the users to search papers in nine selected languages. Currently, only the ab...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00274
更新日期:2020-07-27 00:00:00
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 n...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00347
更新日期:2018-08-27 00:00:00
abstract::Increasing protein kinase C (PKC) activity is of potential therapeutic value. Its activation involves an interaction between the C1 domain and diacylglycerol (DAG) at intracellular membrane surfaces; DAG mimetics hold promise as new drugs. We previously developed the isophthalate derivative HMI-1a3, an effective but h...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00624
更新日期:2020-11-23 00:00:00
abstract::The early stages of drug discovery rely on hit-to-lead programs, where initial hits undergo partial optimization to improve binding affinities for their biological target. This is an expensive and time-consuming process, requiring multiple iterations of trial and error designs, an ideal scenario for applying computer ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00938
更新日期:2020-03-23 00:00:00
abstract::The prediction of Log P is usually accomplished using either substructure or whole-molecule approaches. However, these methods are complicated, and previous whole-molecule approaches have not been successful for the prediction of Log P in very complex molecules. The observed chemical shifts in nuclear magnetic resonan...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci049643e
更新日期:2005-03-01 00:00:00
abstract::Ergotamine (ERG) and dihydroergotamine (DHE), common migraine drugs, have small structural differences but lead to clinically important distinctions in their pharmacological profiles. For example, DHE is less potent than ERG by about 10-fold at the 5-hydroxytrptamine receptor 1B (5-HT1B). Although the high-resolution ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b01082
更新日期:2020-03-23 00:00:00
abstract::The predictive performances of MC4PC were evaluated using its learning machine functionality. Its superior characteristics are demonstrated in this following up study using the newly published Ames mutagenicity benchmark set. ...
journal_title:Journal of chemical information and modeling
pub_type: 评论,信件
doi:10.1021/ci1000899
更新日期:2010-09-27 00:00:00
abstract::Inhibition of protein-protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structura...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00103
更新日期:2015-08-24 00:00:00
abstract::The study of chromatographic retention of natural products can be used to increase their identification speed in complex biological matrices. In this work, six variables were used to study the retention behavior in reversed phase liquid chromatography of 39 sesquiterpene lactones (SL) from an in-house database using c...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci500581q
更新日期:2015-01-26 00:00:00
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
更新日期:2011-10-24 00:00:00
abstract::The present study focuses on the determination of the biologically significant N-acetylneuraminic acid (NANA) drug binding interaction mechanism between bovine serum albumin (BSA) and human α-1 acid glycoprotein (HAG) using various optical spectroscopy and computational methods. The steady state fluorescence spectrosc...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.8b00558
更新日期:2019-01-28 00:00:00
abstract::Databases of small, potentially bioactive molecules are ubiquitous across the industry and academia. Designed such that each unique compound should appear only once, the multiplicity of ways in which many compounds can be represented means that these databases require methods for standardizing the representation of ch...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.0c00232
更新日期:2020-08-24 00:00:00
abstract::A comprehensive safety evaluation of chemicals should require toxicity assessment in both the aquatic and terrestrial test species. Due to the application practices and nature of chemical pesticides, the avian toxicity testing is considered as an essential requirement in the risk assessment process. In this study, tre...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00139
更新日期:2015-07-27 00:00:00
abstract::Molecular channel exploration perseveres to be the prominent solution for eliciting structure and accessibility of active site and other internal spaces of macromolecules. The volume and silhouette characterization of these channels provides answers for the issues of substrate access and ligand swapping between the ob...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci200584f
更新日期:2012-02-27 00:00:00
abstract::Extending the original training data with simulated unobserved data points has proven powerful to increase both the generalization ability of predictive models and their robustness against changes in the structure of data (e.g., systematic drifts in the response variable) in diverse areas such as the analysis of spect...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00570
更新日期:2015-12-28 00:00:00
abstract::Large corpora of kinase small molecule inhibitor data are accessible to public sector research from thousands of journal article and patent publications. These data have been generated employing a wide variety of assay methodologies and experimental procedures by numerous laboratories. Here we ask the question how app...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300403k
更新日期:2013-01-28 00:00:00
abstract::Optimization of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly because of its lack of accuracy and reproducibili...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.6b00780
更新日期:2017-04-24 00:00:00
abstract::A model for prediction of percent intestinal absorption (%Abs) of neutral molecules was developed based upon surface charges of the molecule calculated by density functional theory (DFT). The surface charges are decomposed into sigma moments which are correlated to a partition coefficient representing transfer of the ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci049653f
更新日期:2005-09-01 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::3-Phosphoinositide-dependent protein kinase-1 (PDK1) is a promising target for developing novel anticancer drugs. In order to understand the structure-activity correlation of indolinone-based PDK1 inhibitors, we have carried out a combined molecular docking and three-dimensional quantitative structure-activity relatio...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci800147v
更新日期:2008-09-01 00:00:00
abstract::TAMkin is a program for the calculation and analysis of normal modes, thermochemical properties and chemical reaction rates. At present, the output from the frequently applied software programs ADF, CHARMM, CPMD, CP2K, Gaussian, Q-Chem, and VASP can be analyzed. The normal-mode analysis can be performed using a broad ...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci100099g
更新日期:2010-09-27 00:00:00
abstract::Model lipid membranes made from binary mixtures of dimyristoylphosphatidylcholine/dipalmitoylphosphatidylcholine (DMPC/DPPC) and dimyristoylphosphatidylcholine/cholesterol (DMPC/Chol) exhibit coexistence of diverse lipid phases at appropriate temperature and composition. Since lipids in different phases show different...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci0501793
更新日期:2005-11-01 00:00:00
abstract::Peptide libraries allow researchers to quickly find hundreds of peptide sequences with a desired property. Currently, the large amount of data generated from peptide libraries is analyzed by hand, where researchers search for repeating patterns in the peptide sequences. Such patterns are called motifs. In this work, w...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci300484q
更新日期:2013-02-25 00:00:00
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...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci700474a
更新日期:2008-07-01 00:00:00
abstract::Antimicrobial peptides (AMPs) have emerged as promising therapeutic alternatives to fight against the diverse infections caused by different pathogenic microorganisms. In this context, theoretical approaches in bioinformatics have paved the way toward the creation of several in silico models capable of predicting anti...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.5b00630
更新日期:2016-03-28 00:00:00
abstract::Most of the common molecular descriptors have numerous different implementations. This can influence the results of compound prioritization based on the multiparameter assessment (MPA) approach that allows a medicinal chemist to simultaneously analyze and achieve the desired balance of the diverse and often conflictin...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.7b00734
更新日期:2018-05-29 00:00:00
abstract::The emergence of multidrug-resistant Staphylococcus aureus (S. aureus) makes the treatment of infectious diseases in hospitals more difficult and increases the mortality of the patients. In this study, we attempted to identify novel potent antibiotic candidate compounds against S. aureus dihydrofolate reductase (saDHF...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/ci400686d
更新日期:2014-04-28 00:00:00
abstract::Acetohydroxyacid synthase (AHAS) is a thiamin diphosphate-dependent enzyme involved in the biosynthesis of valine, leucine, isoleucine, and lysine. Experimental evidence has shown that mutation of the Gln202 residue results in a decrease in the enzymatic activity, thus suggesting the main role of the carboligation cat...
journal_title:Journal of chemical information and modeling
pub_type: 杂志文章
doi:10.1021/acs.jcim.9b00863
更新日期:2020-02-24 00:00:00