6ey9: Difference between revisions
New page: '''Unreleased structure''' The entry 6ey9 is ON HOLD Authors: Musil, D., Lehmann, M., Buchstaller, H.-P. Description: Estimation of relative drug-target residence times by random accel... |
No edit summary |
||
| (3 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Estimation of relative drug-target residence times by random acceleration molecular dynamics simulation== | |||
<StructureSection load='6ey9' size='340' side='right'caption='[[6ey9]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6ey9]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EY9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EY9 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C4N:~{N}-[(4-chlorophenyl)methyl]-~{N}-methyl-3-[(3-methylphenyl)methyl]-6-oxidanyl-1~{H}-indazole-5-carboxamide'>C4N</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ey9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ey9 OCA], [https://pdbe.org/6ey9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ey9 RCSB], [https://www.ebi.ac.uk/pdbsum/6ey9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ey9 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Drug-target residence time (tau), one of the main determinants of drug efficacy, remains highly challeng-ing to predict computationally and, therefore, is usually not considered in the early stages of drug de-sign. Here, we present an efficient computational method, tau-random acceleration molecular dynamics (tauRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed tauRAMD on a dataset of 70 diverse drug-like ligands of the N-terminal domain of HSP90alpha, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3tau for 78% of the compounds and less than 2.0tau within congeneric series. Analysis of dissociation trajectories reveals features that af-fect ligand unbinding rates, including transient polar interactions and steric hindrance. These results sug-gest that tauRAMD will be widely applicable as a computationally efficient aid to improving drug resi-dence times during lead optimization. | |||
Estimation of drug-target residence times by tau -random acceleration molecular dynamics simulations.,Kokh DB, Amaral M, Bomke J, Gradler U, Musil D, Buchstaller HP, Dreyer MK, Frech M, Lowinski M, Vallee F, Bianciotto M, Rak A, Wade RC J Chem Theory Comput. 2018 May 16. doi: 10.1021/acs.jctc.8b00230. PMID:29768913<ref>PMID:29768913</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6ey9" style="background-color:#fffaf0;"></div> | ||
[[Category: Buchstaller | |||
[[Category: Musil | ==See Also== | ||
*[[Heat Shock Protein structures|Heat Shock Protein structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Buchstaller H-P]] | |||
[[Category: Lehmann M]] | |||
[[Category: Musil D]] | |||
Latest revision as of 15:22, 9 May 2024
Estimation of relative drug-target residence times by random acceleration molecular dynamics simulationEstimation of relative drug-target residence times by random acceleration molecular dynamics simulation
Structural highlights
FunctionHS90A_HUMAN Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedDrug-target residence time (tau), one of the main determinants of drug efficacy, remains highly challeng-ing to predict computationally and, therefore, is usually not considered in the early stages of drug de-sign. Here, we present an efficient computational method, tau-random acceleration molecular dynamics (tauRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed tauRAMD on a dataset of 70 diverse drug-like ligands of the N-terminal domain of HSP90alpha, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3tau for 78% of the compounds and less than 2.0tau within congeneric series. Analysis of dissociation trajectories reveals features that af-fect ligand unbinding rates, including transient polar interactions and steric hindrance. These results sug-gest that tauRAMD will be widely applicable as a computationally efficient aid to improving drug resi-dence times during lead optimization. Estimation of drug-target residence times by tau -random acceleration molecular dynamics simulations.,Kokh DB, Amaral M, Bomke J, Gradler U, Musil D, Buchstaller HP, Dreyer MK, Frech M, Lowinski M, Vallee F, Bianciotto M, Rak A, Wade RC J Chem Theory Comput. 2018 May 16. doi: 10.1021/acs.jctc.8b00230. PMID:29768913[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||