scholarly journals Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors

2018 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Rachel J. Harding ◽  
Ivan Franzoni ◽  
Mani Ravichandran ◽  
Mandeep K. Mann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Zinc Finger ◽  
Proteasome Inhibitors ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Activity Relationship ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

AbstractHDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation, and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of a HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155 are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens-up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

scholarly journals Identification and Structure–Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors

2018 ◽  
Vol 61 (10) ◽  
pp. 4517-4527 ◽  
Author(s):  
Renato Ferreira de Freitas ◽  
Rachel J. Harding ◽  
Ivan Franzoni ◽  
Mani Ravichandran ◽  
Mandeep K. Mann ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Structure Activity Relationship ◽  
Binding Domain ◽  
Activity Relationship ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Relationship Of

scholarly journals Discovery of small molecule antagonists of the USP5 zinc finger ubiquitin-binding domain

2019 ◽  
Author(s):  
Mandeep K. Mann ◽  
Ivan Franzoni ◽  
Renato Ferreira de Freitas ◽  
Wolfram Tempel ◽  
Scott Houliston ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Allosteric Modulation ◽  
Binding Domain ◽  
Signalling Pathways ◽  
Chemical Library ◽  
Polyubiquitin Chains ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Health And Disease

AbstractUSP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve ubiquitin-specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signalling pathways in health and disease.

scholarly journals Structure Activity Relationship of USP5 Allosteric Inhibitors

2021 ◽  
Author(s):  
Mandeep K Mann ◽  
Carlos A Zepeda-Velazquez ◽  
Hector G Alvarez ◽  
Aiping Dong ◽  
Taira Kiyota ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Chemical Probe ◽  
Structural Framework ◽  
Structure Activity ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain ◽  
Multiple Ligands

USP5 is a deubiquitinase that has been implicated in a range of diseases, including cancer, but no USP5-targeting chemical probe has been reported to date. Here, we present the progression of a chemical series that occupies the C-terminal ubiquitin-binding site of a poorly characterized zinc-finger ubiquitin binding domain (ZnF-UBD) of USP5 and allosterically inhibits the catalytic activity of the enzyme. Systematic exploration of the structure-activity relationship, complemented with crystallographic characterization of the ZnF-UBD bound to multiple ligands, led to the identification of 64, which binds to the USP5 ZnF-UBD with a KD of 2.8 μM. 64 is selective over the structurally similar ZnF-UBD domain of HDAC6 and inhibits USP5 catalytic activity in vitro with an IC50 of 26 μM. This study provides a chemical and structural framework for the discovery of a chemical probe to delineate USP5 function in cells.

Structure–activity relationship of boronic acid derivatives of tyropeptin: Proteasome inhibitors

2010 ◽  
Vol 20 (19) ◽  
pp. 5839-5842 ◽  
Author(s):  
Takumi Watanabe ◽  
Hikaru Abe ◽  
Isao Momose ◽  
Yoshikazu Takahashi ◽  
Daishiro Ikeda ◽  
...  
Keyword(s):  
Boronic Acid ◽  
Proteasome Inhibitors ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Boronic Acid Derivatives ◽  
Relationship Of ◽  
Derivatives Of

scholarly journals The Zinc Finger of NEMO Is a Functional Ubiquitin-binding Domain

2008 ◽  
Vol 284 (5) ◽  
pp. 2902-2907 ◽  
Author(s):  
Florence Cordier ◽  
Olivera Grubisha ◽  
François Traincard ◽  
Michel Véron ◽  
Muriel Delepierre ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Binding Domain ◽  
Ubiquitin Binding ◽  
Ubiquitin Binding Domain

scholarly journals Discovery of New Hydroxyethylamine Analogs Against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation and Structure-Activity Relationship Studies

2020 ◽  
Author(s):  
Sumit Kumar ◽  
Prem Prakash Sharma ◽  
Uma Shankar ◽  
Dhruv Kumar ◽  
Sanjeev K Joshi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Cysteine Protease ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Dynamics Simulation ◽  
Activity Relationship ◽  
Docking Score ◽  
Structure Activity ◽  
Novel Coronavirus

<p><br></p> <p>A novel coronavirus, SARS-CoV-2 has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of vaccine and potential therapeutics are critically essential. The crystal structure for main protease (M<sup>pro</sup>) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) was recently made available and is considerably similar to previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against 3-chymotrypsin-like cysteine protease (3CL<sup>pro</sup>) enzyme was accomplished and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound <b>16</b> with docking score of -8.955 adhered to drug like parameters, and the Structure-Activity Relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular Dynamics (MD) simulation studies carried out at 100ns supported the stability of <b>16</b> within the binding pocket. Largly, our results supported that this novel compound <b>16</b> binds to the domain I & II, and domain II-III linker of 3CL<sup>pro</sup> protein, suggesting its suitablity as strong candidate for therapeutic discovery against COVID-19. Lead compound <b>16</b> could pave incredible directions for the design of novel 3CL<sup>pro</sup> inhibitors and ultimately therapeutics against COVID-19 disease.</p> <p><br></p> <p> </p>

scholarly journals Deacylcortivazol-like pyrazole regioisomers reveal a more accommodating expanded binding pocket for the glucocorticoid receptor

2021 ◽  
Author(s):  
Jessica A. O. Zimmerman ◽  
Mimi Fang ◽  
Bintou Doumbia ◽  
Alexis Neyman ◽  
Ji Hyeon Cha ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity

Ullmann-like synthesis of deacylcortivazol-like regioisomers reveals a broader than expected structure activity relationship for novel glucocorticoids.

scholarly journals Synthesis and characterization of photoaffinity labelling reagents towards the Hsp90 C-terminal domain

2017 ◽  
Vol 15 (7) ◽  
pp. 1597-1605 ◽  
Author(s):  
Binto Simon ◽  
Xuexia Huang ◽  
Huangxian Ju ◽  
Guoxuan Sun ◽  
Min Yang
Keyword(s):  
Binding Pocket ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Synthesis And Characterization ◽  
Photoaffinity Labelling ◽  
Terminal Domain ◽  
Structure Activity

The synthesis of diazirine type photoaffinity labelling reagents to probe the Hsp90 C-terminal domain binding pocket and the structure–activity relationship. The structure illustrates probe positions only.

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