J Chem Inf Model - Unbinding pathways of GW4064 from human farnesoid X receptor as revealed by molecular dynamics simulations.


{ bind(1733) structur(1185) ligand(1036) }
{ gene(2352) biolog(1181) express(1162) }
{ method(1557) propos(1049) approach(1037) }
{ import(1318) role(1303) understand(862) }
{ model(2220) cell(1177) simul(1124) }
{ model(3480) simul(1196) paramet(876) }
{ howev(809) still(633) remain(590) }
{ studi(1410) differ(1259) use(1210) }
{ perform(1367) use(1326) method(1137) }
{ spatial(1525) area(1432) region(1030) }
{ activ(1138) subject(705) human(624) }
{ use(1733) differ(960) four(931) }
{ can(774) often(719) complex(702) }
{ data(1737) use(1416) pattern(1282) }
{ take(945) account(800) differ(722) }
{ surgeri(1148) surgic(1085) robot(1054) }
{ error(1145) method(1030) estim(1020) }
{ chang(1828) time(1643) increas(1301) }
{ perform(999) metric(946) measur(919) }
{ state(1844) use(1261) util(961) }
{ use(976) code(926) identifi(902) }
{ method(1969) cluster(1462) data(1082) }
{ imag(2830) propos(1344) filter(1198) }
{ network(2748) neural(1063) input(814) }
{ treatment(1704) effect(941) patient(846) }
{ design(1359) user(1324) use(1319) }
{ care(1570) inform(1187) nurs(1089) }
{ search(2224) databas(1162) retriev(909) }
{ data(3963) clinic(1234) research(1004) }
{ research(1085) discuss(1038) issu(1018) }
{ compound(1573) activ(1297) structur(1058) }
{ data(2317) use(1299) case(1017) }
{ data(3008) multipl(1320) sourc(1022) }
{ first(2504) two(1366) second(1323) }
{ time(1939) patient(1703) rate(768) }
{ health(1844) social(1437) communiti(874) }
{ cancer(2502) breast(956) screen(824) }
{ result(1111) use(1088) new(759) }
{ process(1125) use(805) approach(778) }
{ model(3404) distribut(989) bayesian(671) }
{ imag(1947) propos(1133) code(1026) }
{ inform(2794) health(2639) internet(1427) }
{ system(1976) rule(880) can(841) }
{ measur(2081) correl(1212) valu(896) }
{ imag(1057) registr(996) error(939) }
{ sequenc(1873) structur(1644) protein(1328) }
{ method(1219) similar(1157) match(930) }
{ featur(3375) classif(2383) classifi(1994) }
{ imag(2675) segment(2577) method(1081) }
{ patient(2315) diseas(1263) diabet(1191) }
{ studi(2440) review(1878) systemat(933) }
{ motion(1329) object(1292) video(1091) }
{ assess(1506) score(1403) qualiti(1306) }
{ framework(1458) process(801) describ(734) }
{ problem(2511) optim(1539) algorithm(950) }
{ learn(2355) train(1041) set(1003) }
{ concept(1167) ontolog(924) domain(897) }
{ clinic(1479) use(1117) guidelin(835) }
{ algorithm(1844) comput(1787) effici(935) }
{ extract(1171) text(1153) clinic(932) }
{ data(1714) softwar(1251) tool(1186) }
{ control(1307) perform(991) simul(935) }
{ general(901) number(790) one(736) }
{ method(984) reconstruct(947) comput(926) }
{ featur(1941) imag(1645) propos(1176) }
{ case(1353) use(1143) diagnosi(1136) }
{ risk(3053) factor(974) diseas(938) }
{ system(1050) medic(1026) inform(1018) }
{ model(2341) predict(2261) use(1141) }
{ visual(1396) interact(850) tool(830) }
{ studi(1119) effect(1106) posit(819) }
{ blood(1257) pressur(1144) flow(957) }
{ record(1888) medic(1808) patient(1693) }
{ health(3367) inform(1360) care(1135) }
{ monitor(1329) mobil(1314) devic(1160) }
{ ehr(2073) health(1662) electron(1139) }
{ research(1218) medic(880) student(794) }
{ patient(2837) hospit(1953) medic(668) }
{ model(2656) set(1616) predict(1553) }
{ age(1611) year(1155) adult(843) }
{ medic(1828) order(1363) alert(1069) }
{ signal(2180) analysi(812) frequenc(800) }
{ cost(1906) reduc(1198) effect(832) }
{ group(2977) signific(1463) compar(1072) }
{ sampl(1606) size(1419) use(1276) }
{ intervent(3218) particip(2042) group(1664) }
{ patient(1821) servic(1111) care(1106) }
{ use(2086) technolog(871) perceiv(783) }
{ can(981) present(881) function(850) }
{ analysi(2126) use(1163) compon(1037) }
{ structur(1116) can(940) graph(676) }
{ high(1669) rate(1365) level(1280) }
{ drug(1928) target(777) effect(648) }
{ implement(1333) system(1263) develop(1122) }
{ survey(1388) particip(1329) question(1065) }
{ estim(2440) model(1874) function(577) }
{ decis(3086) make(1611) patient(1517) }
{ activ(1452) weight(1219) physic(1104) }
{ method(2212) result(1239) propos(1039) }
{ detect(2391) sensit(1101) algorithm(908) }


Farnesoid X receptor (FXR, NR1H4) is a member of a nuclear receptor superfamily, which plays important roles in bile acid homeostasis, lipoprotein and glucose metabolism, and hepatic regeneration. GW4064 is a potent and selective FXR agonist and has become a tool compound to probe the physiological functions of FXR. Until now, the mechanism of GW4064 entering and leaving the FXR pocket is still poorly understood. Here, we report a computational study of GW4064 unbinding pathways from FXR by using several molecular dynamics (MD) simulation techniques. Based on the crystal structure of FXR in complex with GW4064, conventional MD was first used to refine the binding and check the stability of GW4064 in the FXR pocket. Random acceleration MD simulations were then performed to explore the possible unbinding pathways of GW4064 from FXR. Four main pathway clusters were found, among which three subpathways, namely Paths 2A, 2B, and 1B, were observed most frequently. Multiple steered MD simulations were further employed to estimate the maximum rupture force and the sum of the forces and to characterize the intermediate states of the ligand unbinding process. By comparing the average force profiles and structural changes, Paths 2A and 2B were identified to be the most favorable unbinding pathways. The former is located between the H1-H2 loop and the H5-H6 loop, and the latter is located in the cleft formed by the H5-H6 loop, H6, and H7. Moreover, the residues lining the pathways were analyzed for their roles in ligand unbinding. Based on our results, the possible structural modification strategies on GW4064 were also proposed.

Resumo Limpo

farnesoid x receptor fxr nrh member nuclear receptor superfamili play import role bile acid homeostasi lipoprotein glucos metabol hepat regener gw potent select fxr agonist becom tool compound probe physiolog function fxr now mechan gw enter leav fxr pocket still poor understood report comput studi gw unbind pathway fxr use sever molecular dynam md simul techniqu base crystal structur fxr complex gw convent md first use refin bind check stabil gw fxr pocket random acceler md simul perform explor possibl unbind pathway gw fxr four main pathway cluster found among three subpathway name path b b observ frequent multipl steer md simul employ estim maximum ruptur forc sum forc character intermedi state ligand unbind process compar averag forc profil structur chang path b identifi favor unbind pathway former locat hh loop hh loop latter locat cleft form hh loop h h moreov residu line pathway analyz role ligand unbind base result possibl structur modif strategi gw also propos

Resumos Similares

J Chem Inf Model - Experimentally guided structural modeling and dynamics analysis of Hsp90-p53 interactions: allosteric regulation of the Hsp90 chaperone by a client protein. ( 0,770241614433202 )
J Chem Inf Model - Scoring function based approach for locating binding sites and understanding recognition mechanism of protein-DNA complexes. ( 0,762598793600221 )
J Chem Inf Model - Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations. ( 0,744640614986691 )
J Chem Inf Model - Discovery of a novel selective PPAR ligand with partial agonist binding properties by integrated in silico/in vitro work flow. ( 0,738434598645319 )
Comput Biol Chem - Mutually exclusive binding of APPL(PH) to BAR domain and Reptin regulates ?-catenin dependent transcriptional events. ( 0,731936927385565 )
J Chem Inf Model - Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. ( 0,72819058915335 )
J. Comput. Biol. - Chromatin properties of regulatory DNA probed by manipulation of transcription factors. ( 0,725534790539424 )
Wiley Interdiscip Rev Syst Biol Med - ?-Arrestin-kinase scaffolds: turn them on or turn them off? ( 0,722862930326313 )
J Chem Inf Model - Truncated variants of the GCN4 transcription activator protein bind DNA with dramatically different dynamical motifs. ( 0,720052000726355 )
J Chem Inf Model - Searching the biologically relevantconformation of dopamine: a computational approach. ( 0,719934180455114 )
J Chem Inf Model - Elucidation of conformational states, dynamics, and mechanism of binding in human -opioid receptor complexes. ( 0,719461313457289 )
J Chem Inf Model - Elucidating a key component of cancer metastasis: CXCL12 (SDF-1a) binding to CXCR4. ( 0,714666369967127 )
J Chem Inf Model - Computational studies of darunavir into HIV-1 protease and DMPC bilayer: necessary conditions for effective binding and the role of the flaps. ( 0,714271301854766 )
Comput Biol Chem - Computational analysis of 3'UTR region of CASP3 with respect to miRSNPs and SNPs in targetting miRNAs. ( 0,713313128135442 )
J Chem Inf Model - Computational approaches elucidate the allosteric mechanism of human aromatase inhibition: a novel possible route to Small-molecule regulation of CYP450s activities? ( 0,712392144864271 )
J Chem Inf Model - Molecular modeling and molecular dynamics simulation studies of the GSK3?/ATP/substrate complex: understanding the unique P+4 primed phosphorylation specificity for GSK3? substrates. ( 0,71090338621607 )
J Chem Inf Model - Ligand binding and functional selectivity of L-tryptophan metabolites at the mouse aryl hydrocarbon receptor (mAhR). ( 0,710143171093968 )
Comput Biol Chem - Interactions of iron-sulfur clusters with small peptides: insights into early evolution. ( 0,699579705756165 )
Comput Biol Chem - Halogen bonding in complexes of proteins and non-natural amino acids. ( 0,698715643137291 )
Wiley Interdiscip Rev Syst Biol Med - Protein-membrane interactions: the virtue of minimal systems in systems biology. ( 0,697689445486723 )
Comput Math Methods Med - Membrane protein stability analyses by means of protein energy profiles in case of nephrogenic diabetes insipidus. ( 0,696728954064086 )
Wiley Interdiscip Rev Syst Biol Med - Cell-specific integration of nuclear receptor function at the genome. ( 0,693927721263035 )
Comput Biol Chem - Multiscale modelling to understand the self-assembly mechanism of human ?2-adrenergic receptor in lipid bilayer. ( 0,693920810571436 )
J Chem Inf Model - Quantum mechanical/molecular mechanical study of catalytic mechanism and role of key residues in methylation reactions catalyzed by dimethylxanthine methyltransferase in caffeine biosynthesis. ( 0,690742412771614 )
J Chem Inf Model - Molecular dynamics simulations reveal a novel mechanism for ATP inhibition of insulin degrading enzyme. ( 0,68942049395457 )
Wiley Interdiscip Rev Syst Biol Med - The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation. ( 0,687373233692463 )
J Chem Inf Model - Macrostate identification from biomolecular simulations through time series analysis. ( 0,687015041952969 )
J Chem Inf Model - The large scale conformational change of the human DPP III-substrate prefers the closed form. ( 0,686926677215691 )
J Chem Inf Model - Lipoic acid and dihydrolipoic acid. A comprehensive theoretical study of their antioxidant activity supported by available experimental kinetic data. ( 0,685851963936885 )
J Chem Inf Model - Molecular determinants of binding to the Plasmodium subtilisin-like protease 1. ( 0,685776391608039 )
Wiley Interdiscip Rev Syst Biol Med - Heparan sulfate proteoglycans in healthy and diseased systems. ( 0,681825225503588 )
J Chem Inf Model - Exploring the molecular mechanism of cross-resistance to HIV-1 integrase strand transfer inhibitors by molecular dynamics simulation and residue interaction network analysis. ( 0,679199980432376 )
J Chem Inf Model - Three descriptor model sets a high standard for the CSAR-NRC HiQ benchmark. ( 0,678513767242166 )
J Chem Inf Model - Autoinhibitory mechanism for the mutation-induced impaired FGF9 signaling. ( 0,674129869949646 )
J Chem Inf Model - Dynamics of noncovalent interactions in all-a and all-? class proteins: implications for the stability of amyloid aggregates. ( 0,673525704017666 )
Comput. Biol. Med. - Predicting miRNA-mediated gene silencing mode based on miRNA-target duplex features. ( 0,672934206125166 )
J Chem Inf Model - Molecular dynamics approach to probe the allosteric inhibition of PTP1B by chlorogenic and cichoric acid. ( 0,672918609021509 )
J Chem Inf Model - Thermodynamic characterization of new positive allosteric modulators binding to the glutamate receptor A2 ligand-binding domain: combining experimental and computational methods unravels differences in driving forces. ( 0,671573710971987 )
J Chem Inf Model - Key binding and susceptibility of NS3/4A serine protease inhibitors against hepatitis C virus. ( 0,669211757023226 )
J Chem Inf Model - Molecular dynamic behavior and binding affinity of flavonoid analogues to the cyclin dependent kinase 6/cyclin D complex. ( 0,667953109386831 )
J Chem Inf Model - Inhibitor and substrate binding by angiotensin-converting enzyme: quantum mechanical/molecular mechanical molecular dynamics studies. ( 0,667636858846531 )
J Chem Inf Model - Insights into the conformational switching mechanism of the human vascular endothelial growth factor receptor type 2 kinase domain. ( 0,665514344992843 )
J Chem Inf Model - Theoretical studies on the interactions and interferences of HIV-1 glycoprotein gp120 and its coreceptor CCR5. ( 0,664671303568871 )
J Am Med Inform Assoc - A rational free energy-based approach to understanding and targeting disease-causing missense mutations. ( 0,664498639244989 )
J Chem Inf Model - Molecular modeling of neurokinin B and tachykinin NK3 receptor complex. ( 0,663177328344543 )
Brief. Bioinformatics - Systematic analysis of the Plk-mediated phosphoregulation in eukaryotes. ( 0,662505869520657 )
J Chem Inf Model - L-arginine binding to human inducible nitric oxide synthase: an antisymmetric funnel route toward isoform-specific inhibitors? ( 0,661409880410551 )
J Chem Inf Model - Elucidation of allosteric inhibition mechanism of 2-Cys human peroxiredoxin by molecular modeling. ( 0,660449925685943 )
J Chem Inf Model - Unbinding pathways of VEGFR2 inhibitors revealed by steered molecular dynamics. ( 0,659231275413699 )
J Chem Inf Model - Molecular dynamics simulation and free energy calculation studies of the binding mechanism of allosteric inhibitors with p38a MAP kinase. ( 0,65863361619082 )
J Chem Inf Model - 3D structure prediction of TAS2R38 bitter receptors bound to agonists phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP). ( 0,658007107441813 )
J Chem Inf Model - Structural insights into the molecular basis of the ligand promiscuity. ( 0,657673761690594 )
J Chem Inf Model - Studies on the interactions between ?2 adrenergic receptor and Gs protein by molecular dynamics simulations. ( 0,656852063356206 )
J Chem Inf Model - Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction. ( 0,654929366973202 )
J Chem Inf Model - Exploring inhibitor release pathways in histone deacetylases using random acceleration molecular dynamics simulations. ( 0,654837275415738 )
Comput Math Methods Med - Revealing -1 programmed ribosomal frameshifting mechanisms by single-molecule techniques and computational methods. ( 0,6533089510326 )
Comput Biol Chem - Computational simulation of ligand docking to L-type pyruvate kinase subunit. ( 0,652204928961012 )
Comput. Biol. Med. - An investigation of molecular dynamics simulation and molecular docking: interaction of citrus flavonoids and bovine ?-lactoglobulin in focus. ( 0,652203694136704 )
J Chem Inf Model - Docking server for the identification of heparin binding sites on proteins. ( 0,652135371672497 )
Comput. Biol. Med. - Genome-wide identification and structure-function studies of proteases and protease inhibitors in Cicer arietinum (chickpea). ( 0,652094832254958 )
Comput Biol Chem - The human olfactory receptor 17-40: requisites for fitting into the binding pocket. ( 0,651748297106369 )
J Chem Inf Model - Perturbation of fluid dynamics properties of water molecules during G protein-coupled receptor-ligand recognition: the human A2A adenosine receptor as a key study. ( 0,651107575140599 )
J Chem Inf Model - Study of Tamiflu sensitivity to variants of A/H5N1 virus using different force fields. ( 0,650501958263346 )
J. Comput. Biol. - Informational requirements for transcriptional regulation. ( 0,650409911503922 )
J Biomed Inform - miRWalk--database: prediction of possible miRNA binding sites by walking the genes of three genomes. ( 0,649263077760597 )
J Chem Inf Model - Interference of boswellic acids with the ligand binding domain of the glucocorticoid receptor. ( 0,649055217054377 )
J Chem Inf Model - Computational screening and selection of cyclic peptide hairpin mimetics by molecular simulation and kinetic network models. ( 0,648288037252255 )
Brief. Bioinformatics - A model-free approach for detecting interactions in genetic association studies. ( 0,647761615697921 )
J Chem Inf Model - Computational rationale for the selective inhibition of the herpes simplex virus type 1 uracil-DNA glycosylase enzyme. ( 0,647321296928438 )
J Chem Inf Model - Conformational determinants of the activity of antiproliferative factor glycopeptide. ( 0,646769213882361 )
J Chem Inf Model - Switchable nonlinear optical properties of 5-monocyclopentadienylmetal complexes: a DFT approach. ( 0,646662157313506 )
J Chem Inf Model - Molecular mechanism-based network-like similarity graphs reveal relationships between different types of receptor ligands and structural changes that determine agonistic, inverse-agonistic, and antagonistic effects. ( 0,646525110690785 )
J Chem Inf Model - How important is the synclinal conformation of sulfonylureas to explain the inhibition of AHAS: a theoretical study. ( 0,646130362776241 )
Comput Biol Chem - On the modelling and analysis of the regulatory network of dengue virus pathogenesis and clearance. ( 0,645527027781099 )
J Chem Inf Model - Structural basis of specific binding between Aurora A and TPX2 by molecular dynamics simulations. ( 0,644533764095815 )
Comput Biol Chem - Consensus in silico computational modelling of the p22phox subunit of the NADPH oxidase. ( 0,644128887334909 )
J Chem Inf Model - Subtype selectivity of dopamine receptor ligands: insights from structure and ligand-based methods. ( 0,644030009130099 )
Comput Math Methods Med - Identification and functional annotation of genome-wide ER-regulated genes in breast cancer based on ChIP-Seq data. ( 0,643974691997208 )
J Chem Inf Model - Exploring protein kinase conformation using swarm-enhanced sampling molecular dynamics. ( 0,643797120980378 )
Comput Biol Chem - A dynamic view to the modulation of phosphorylation and O-GlcNAcylation by inhibition of O-GlcNAcase. ( 0,643406896799173 )
J. Comput. Biol. - Protein-specific scoring method for ligand discovery. ( 0,643385284824683 )
J Chem Inf Model - Unraveling the allosteric inhibition mechanism of PTP1B by free energy calculation based on umbrella sampling. ( 0,643326048566306 )
Comput. Biol. Med. - Analysis of the structure of calpain-10 and its interaction with the protease inhibitor SNJ-1715. ( 0,642880228600165 )
J Chem Inf Model - Computational analysis of human OGA structure in complex with PUGNAc and NAG-thiazoline derivatives. ( 0,641805905716749 )
J Chem Inf Model - Reproducing crystal binding modes of ligand functional groups using Site-Identification by Ligand Competitive Saturation (SILCS) simulations. ( 0,64171741618568 )
J. Comput. Biol. - Exploring the landscape of protein-ligand interaction energy using probabilistic approach. ( 0,641531942164215 )
J Chem Inf Model - GalaxyDock: protein-ligand docking with flexible protein side-chains. ( 0,641164961696153 )
J. Comput. Biol. - A new role for the nonpathogenic nonsynonymous single-nucleotide polymorphisms of acetylcholinesterase in the treatment of Alzheimer's disease: a computational study. ( 0,640919092814384 )
Comput Biol Chem - Molecular dynamics studies of ?-hairpin folding with the presence of the sodium ion. ( 0,640917352129836 )
Wiley Interdiscip Rev Syst Biol Med - Protein microarrays for genome-wide posttranslational modification analysis. ( 0,640570047420887 )
J Chem Inf Model - Regulation of JAK2 activation by Janus homology 2: evidence from molecular dynamics simulations. ( 0,639086934030639 )
J Chem Inf Model - Insights into the role of magnesium triad in myo-inositol monophosphatase: metal mechanism, substrate binding, and lithium therapy. ( 0,638949977976933 )
J Chem Inf Model - Computational prediction of structure-activity relationships for the binding of aminocyclitols to ?-glucocerebrosidase. ( 0,638724663324478 )
J Chem Inf Model - Top leads for swine influenza A/H1N1 virus revealed by steered molecular dynamics approach. ( 0,638602027432977 )
J Chem Inf Model - Molecular modeling of p38a mitogen-activated protein kinase inhibitors through 3D-QSAR and molecular dynamics simulations. ( 0,63835387161989 )
J Chem Inf Model - Docking validation resources: protein family and ligand flexibility experiments. ( 0,637983795482082 )
J Chem Inf Model - Evaluation of several two-step scoring functions based on linear interaction energy, effective ligand size, and empirical pair potentials for prediction of protein-ligand binding geometry and free energy. ( 0,637649048962795 )
J Chem Inf Model - Investigation on the effect of key water molecules on docking performance in CSARdock exercise. ( 0,637112642202064 )
J Chem Inf Model - Analyzing the molecular basis of enzyme stability in ethanol/water mixtures using molecular dynamics simulations. ( 0,636750962191225 )
J Chem Inf Model - Application of the docking program SOL for CSAR benchmark. ( 0,63666598808123 )