6hhr
Hsp90 in complex with 5-(2,4-Dihydroxy-phenyl)-4-(2-fluoro-phenyl)-2,4-dihydro-[1,2,4]triazole-3-thione
Structural highlights
Function[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.[1] [2] Publication Abstract from PubMedComputational approaches currently assist medicinal chemistry through the entire drug discovery pipeline. However, while several computational tools and strategies are available to predict binding affinity, predicting the drug-target binding kinetics is still a matter of ongoing research. Here, we challenge scaled molecular dynamics simulations to assess the off-rates for a series of structurally diverse inhibitors of the heat shock protein 90 (Hsp90) covering 3 orders of magnitude in their experimental residence times. The derived computational predictions are in overall good agreement with experimental data. Aside from the estimation of exit times, unbinding pathways were assessed through dimensionality reduction techniques. The data analysis framework proposed in this work could lead to better understanding of the mechanistic aspects related to the observed kinetic behavior. Predicting Residence Time and Drug Unbinding Pathway through Scaled Molecular Dynamics.,Schuetz DA, Bernetti M, Bertazzo M, Musil D, Eggenweiler HM, Recanatini M, Masetti M, Ecker GF, Cavalli A J Chem Inf Model. 2019 Jan 28;59(1):535-549. doi: 10.1021/acs.jcim.8b00614. Epub , 2018 Dec 13. PMID:30500211[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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