Structural basis for the mutation-induced dysfunction of human CYP2J2: a computational study.

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 Model

authors

Cong S,Ma XT,Li YX,Wang JF

doi

10.1021/ci400003p

subject

Has Abstract

pub_date

2013-06-24 00:00:00

pages

1350-7

issue

6

eissn

1549-9596

issn

1549-960X

journal_volume

53

pub_type

杂志文章
  • A Selectivity Study of FFAR4/FFAR1 Agonists by Molecular Modeling.

    abstract::FFAR4 has been considered as a potential target for metabolic diseases, including diabetes. Some compounds with biphenyl scaffold, represented by compound SR13 reported by our group, showed significant FFAR4 selectivity. However, the molecular basis for their selectivity has not been definitely disclosed. This study p...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.9b00735

    authors: Zhang X,Sun H,Wen X,Yuan H

    更新日期:2019-10-28 00:00:00

  • Interpretation of the binding affinities of PTP1B inhibitors with the MM-GB/SA method and the X-score scoring function.

    abstract::We have studied the binding affinities of a set of 45 small-molecule inhibitors to protein tyrosine phosphatase 1B (PTP1B) through computational approaches. All of these compounds share a common oxalylamino benzoic acid (OBA) moiety. The complex structure of each compound was modeled by using the GOLD program plus the...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci8004429

    authors: Zhang X,Li X,Wang R

    更新日期:2009-04-01 00:00:00

  • Evaluating Unexpectedly Short Non-covalent Distances in X-ray Crystal Structures of Proteins with Electronic Structure Analysis.

    abstract::We investigate unexpectedly short non-covalent distances (<85% of the sum of van der Waals radii) in X-ray crystal structures of proteins. We curate over 11 000 high-quality protein crystal structures and an ultra-high-resolution (1.2 Å or better) subset containing >900 structures. Although our non-covalent distance c...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.9b00144

    authors: Qi HW,Kulik HJ

    更新日期:2019-05-28 00:00:00

  • Molecular Simulation of αvβ6 Integrin Inhibitors.

    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

    authors: Guest EE,Oatley SA,Macdonald SJF,Hirst JD

    更新日期:2020-11-23 00:00:00

  • Accurate Estimation of pKb Values for Amino Groups from Surface Electrostatic Potential (VS,min) Calculations: The Isoelectric Points of Amino Acids as a Case Study.

    abstract::Theoretical calculation of equilibrium dissociation constants is a very computationally demanding and time-consuming process since it requires an extremely accurate computation of the solvation free energy changes for each of the species involved. By correlating the minimum surface electrostatic potential (VS,min) on ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.9b01173

    authors: Sandoval-Lira J,Mondragón-Solórzano G,Lugo-Fuentes LI,Barroso-Flores J

    更新日期:2020-03-23 00:00:00

  • Ranking Reversible Covalent Drugs: From Free Energy Perturbation to Fragment Docking.

    abstract::Reversible covalent inhibitors have drawn increasing attention in drug design, as they are likely more potent than noncovalent inhibitors and less toxic than covalent inhibitors. Despite those advantages, the computational prediction of reversible covalent binding presents a formidable challenge because the binding pr...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.8b00959

    authors: Zhang H,Jiang W,Chatterjee P,Luo Y

    更新日期:2019-05-28 00:00:00

  • iUmami-SCM: A Novel Sequence-Based Predictor for Prediction and Analysis of Umami Peptides Using a Scoring Card Method with Propensity Scores of Dipeptides.

    abstract::Umami or the taste of monosodium glutamate represents one of the major attractive taste modalities in humans. Therefore, knowledge about biophysical and biochemical properties of the umami taste is important for both scientific research and the food industry. Experimental approaches for predicting umami peptides are l...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.0c00707

    authors: Charoenkwan P,Yana J,Nantasenamat C,Hasan MM,Shoombuatong W

    更新日期:2020-12-28 00:00:00

  • Sensitivity of Folding Molecular Dynamics Simulations to Even Minor Force Field Changes.

    abstract::We examine the sensitivity of folding molecular dynamics simulations on the choice between three variants of the same force field (the AMBER99SB force field and its ILDN, NMR-ILDN, and STAR-ILDN variants). Using two different peptide systems (a marginally stable helical peptide and a β-hairpin) and a grand total of mo...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.6b00493

    authors: Serafeim AP,Salamanos G,Patapati KK,Glykos NM

    更新日期:2016-10-24 00:00:00

  • H274Y's Effect on Oseltamivir Resistance: What Happens Before the Drug Enters the Binding Site.

    abstract::Increased reports of oseltamivir (OTV)-resistant strains of the influenza virus, such as the H274Y mutation on its neuraminidase (NA), have created some cause for concern. Many studies have been conducted in the attempt to uncover the mechanism of OTV resistance in H274Y NA. However, most of the reported studies on H2...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.5b00331

    authors: Yusuf M,Mohamed N,Mohamad S,Janezic D,Damodaran KV,Wahab HA

    更新日期:2016-01-25 00:00:00

  • Efficient Corrections for DFT Noncovalent Interactions Based on Ensemble Learning Models.

    abstract::Machine learning has exhibited powerful capabilities in many areas. However, machine learning models are mostly database dependent, requiring a new model if the database changes. Therefore, a universal model is highly desired to accommodate the widest variety of databases. Fortunately, this universality may be achieve...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.8b00878

    authors: Li W,Miao W,Cui J,Fang C,Su S,Li H,Hu L,Lu Y,Chen G

    更新日期:2019-05-28 00:00:00

  • Performance evaluation of 2D fingerprint and 3D shape similarity methods in virtual screening.

    abstract::Virtual screening (VS) can be accomplished in either ligand- or structure-based methods. In recent times, an increasing number of 2D fingerprint and 3D shape similarity methods have been used in ligand-based VS. To evaluate the performance of these ligand-based methods, retrospective VS was performed on a tailored dir...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci300030u

    authors: Hu G,Kuang G,Xiao W,Li W,Liu G,Tang Y

    更新日期:2012-05-25 00:00:00

  • Role of halogen bonds in thyroid hormone receptor selectivity: pharmacophore-based 3D-QSSR studies.

    abstract::Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TRalpha and TRbeta. Several pharmacological effects mediated by TRbeta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TRbeta activation may el...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci900316e

    authors: Valadares NF,Salum LB,Polikarpov I,Andricopulo AD,Garratt RC

    更新日期:2009-11-01 00:00:00

  • First Multitarget Chemo-Bioinformatic Model To Enable the Discovery of Antibacterial Peptides against Multiple Gram-Positive Pathogens.

    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

    authors: Speck-Planche A,Kleandrova VV,Ruso JM,Cordeiro MN

    更新日期:2016-03-28 00:00:00

  • Structure-based discovery of novel non-nucleosidic DNA alkyltransferase inhibitors: virtual screening and in vitro and in vivo activities.

    abstract::The human DNA-repair O (6)-alkylguanine DNA alkyltransferase (MGMT or hAGT) protein protects DNA from environmental alkylating agents and also plays an important role in tumor resistance to chemotherapy treatment. Available inhibitors, based on pseudosubstrate analogs, have been shown to induce substantial bone marrow...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci700447r

    authors: Ruiz FM,Gil-Redondo R,Morreale A,Ortiz AR,Fábrega C,Bravo J

    更新日期:2008-04-01 00:00:00

  • Homology model-guided 3D-QSAR studies of HIV-1 integrase inhibitors.

    abstract::In the present study, we report the exploration of binding modes of potent HIV-1 integrase (IN) inhibitors MK-0518 (raltegravir) and GS-9137 (elvitegravir) as well as chalcone and related amide IN inhibitors we recently synthesized and the development of 3D-QSAR models for integrase inhibition. Homology models of DNA-...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci200485a

    authors: Sharma H,Cheng X,Buolamwini JK

    更新日期:2012-02-27 00:00:00

  • Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators.

    abstract::Voltage-gated sodium channels (VGSC) are attractive targets for drug discovery because of the broad therapeutic potential of their modulators. On the basis of the structure of marine alkaloid clathrodin, we have recently discovered novel subtype-selective VGSC modulators I and II that were used as starting points for ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci400505e

    authors: Tomašić T,Hartzoulakis B,Zidar N,Chan F,Kirby RW,Madge DJ,Peigneur S,Tytgat J,Kikelj D

    更新日期:2013-12-23 00:00:00

  • Partitioning of pi-electrons in rings for Clar structures of benzenoid hydrocarbons.

    abstract::Resonance structures of polycyclic aromatic hydrocarbons can be associated with numerical formulas by assigning pi-electrons of C=C double bonds to individual benzenoid rings. Each C=C double bond in a resonance structure assigns two pi-electrons to a ring in a fused-benzenoid system if it is not shared by adjacent ri...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci050196s

    authors: Randić M,Balaban AT

    更新日期:2006-01-01 00:00:00

  • Structure-based design and screen of novel inhibitors for class II 3-hydroxy-3-methylglutaryl coenzyme A reductase from Streptococcus pneumoniae.

    abstract::3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is a primary target in the current clinical treatment of hypercholesterolemia with specific inhibitors of "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzyme, which are well-known as...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci300163v

    authors: Li D,Gui J,Li Y,Feng L,Han X,Sun Y,Sun T,Chen Z,Cao Y,Zhang Y,Zhou L,Hu X,Ren Y,Wan J

    更新日期:2012-07-23 00:00:00

  • Random Forest Refinement of Pairwise Potentials for Protein-Ligand Decoy Detection.

    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

    authors: Pei J,Zheng Z,Kim H,Song LF,Walworth S,Merz MR,Merz KM Jr

    更新日期:2019-07-22 00:00:00

  • Criterion for evaluating the predictive ability of nonlinear regression models without cross-validation.

    abstract::We propose predictive performance criteria for nonlinear regression models without cross-validation. The proposed criteria are the determination coefficient and the root-mean-square error for the midpoints between k-nearest-neighbor data points. These criteria can be used to evaluate predictive ability after the regre...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci4003766

    authors: Kaneko H,Funatsu K

    更新日期:2013-09-23 00:00:00

  • Physics-based scoring of protein-ligand complexes: enrichment of known inhibitors in large-scale virtual screening.

    abstract::We demonstrate that using an all-atom molecular mechanics force field combined with an implicit solvent model for scoring protein-ligand complexes is a promising approach for improving inhibitor enrichment in the virtual screening of large compound databases. The rescoring method is evaluated by the extent to which kn...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci0502855

    authors: Huang N,Kalyanaraman C,Irwin JJ,Jacobson MP

    更新日期:2006-01-01 00:00:00

  • Spatial sign preprocessing: a simple way to impart moderate robustness to multivariate estimators.

    abstract::The spatial sign is a multivariate extension of the concept of sign. Recently multivariate estimators of covariance structures based on spatial signs have been examined by various authors. These new estimators are found to be robust to outlying observations. From a computational point of view, estimators based on spat...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci050498u

    authors: Serneels S,De Nolf E,Van Espen PJ

    更新日期:2006-05-01 00:00:00

  • Structure-activity relationships in non-ligand binding pocket (non-LBP) diarylhydrazide antiandrogens.

    abstract::We report the synthesis and a study of the structure-activity relationships of a new series of diarylhydrazides as potential selective non-ligand binding pocket androgen receptor antagonists. Their biological activity as antiandrogens in the context of the development of treatments for castration resistant prostate ca...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci400189m

    authors: Caboni L,Egan B,Kelly B,Blanco F,Fayne D,Meegan MJ,Lloyd DG

    更新日期:2013-08-26 00:00:00

  • Discovery and Evaluation of Anti-Fibrinolytic Plasmin Inhibitors Derived from 5-(4-Piperidyl)isoxazol-3-ol (4-PIOL).

    abstract::Inhibition of plasmin has been found to effectively reduce fibrinolysis and to avoid hemorrhage. This can be achieved by addressing its kringle 1 domain with the known drug and lysine analogue tranexamic acid. Guided by shape similarities toward a previously discovered lead compound, 5-(4-piperidyl)isoxazol-3-ol, a se...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.7b00255

    authors: Schmidt TC,Eriksson PO,Gustafsson D,Cosgrove D,Frølund B,Boström J

    更新日期:2017-07-24 00:00:00

  • Influence of protonation, tautomeric, and stereoisomeric states on protein-ligand docking results.

    abstract::In this work, we present a systematical investigation of the influence of ligand protonation states, stereoisomers, and tautomers on results obtained with the two protein-ligand docking programs GOLD and PLANTS. These different states were generated with a fully automated tool, called SPORES (Structure PrOtonation and...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci800420z

    authors: ten Brink T,Exner TE

    更新日期:2009-06-01 00:00:00

  • Cheminformatics Modeling of Adverse Drug Responses by Clinically Relevant Mutants of Human Androgen Receptor.

    abstract::The human androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of prostate cancer (PCa). Many forms of castration-resistant prostate cancer (CRPC) still rely on the AR for survival. Currently used antiandrogens face clinical limitations as drug ...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.6b00400

    authors: Paul N,Carabet LA,Lallous N,Yamazaki T,Gleave ME,Rennie PS,Cherkasov A

    更新日期:2016-12-27 00:00:00

  • Coarse-Grained Prediction of Peptide Binding to G-Protein Coupled Receptors.

    abstract::In this study, we used the Martini Coarse-Grained model with no applied restraints to predict the binding mode of some peptides to G-Protein Coupled Receptors (GPCRs). Both the Neurotensin-1 and the chemokine CXCR4 receptors were used as test cases. Their ligands, NTS8-13 and CVX15 peptides, respectively, were initial...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.6b00503

    authors: Delort B,Renault P,Charlier L,Raussin F,Martinez J,Floquet N

    更新日期:2017-03-27 00:00:00

  • Leave-cluster-out cross-validation is appropriate for scoring functions derived from diverse protein data sets.

    abstract::With the emergence of large collections of protein-ligand complexes complemented by binding data, as found in PDBbind or BindingMOAD, new opportunities for parametrizing and evaluating scoring functions have arisen. With huge data collections available, it becomes feasible to fit scoring functions in a QSAR style, i.e...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci100264e

    authors: Kramer C,Gedeck P

    更新日期:2010-11-22 00:00:00

  • GPCR-Bench: A Benchmarking Set and Practitioners' Guide for G Protein-Coupled Receptor Docking.

    abstract::Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/acs.jcim.5b00660

    authors: Weiss DR,Bortolato A,Tehan B,Mason JS

    更新日期:2016-04-25 00:00:00

  • Protein kinases: docking and homology modeling reliability.

    abstract::A database of about 700 high-resolution kinase structures was used to test the reliability of 17 docking procedures (using six docking software packages) by means of self- and cross-docking studies. The analysis of about 80 000 docking calculations suggests that the docking of an unknown ligand into a kinase has a pro...

    journal_title:Journal of chemical information and modeling

    pub_type: 杂志文章

    doi:10.1021/ci100161z

    authors: Tuccinardi T,Botta M,Giordano A,Martinelli A

    更新日期:2010-08-23 00:00:00