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.

scholarly journals Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

2012 ◽  
Vol 8 ◽  
pp. 841-849 ◽  
Author(s):  
Chao Che ◽  
Song Li ◽  
Bo Yang ◽  
Shengchang Xin ◽  
Zhixiong Yu ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Structure Activity Relationship ◽  
Hedgehog Pathway ◽  
Activity Relationship ◽  
Synthesis And Characterization ◽  
Important Class ◽  
Diversity Oriented Synthesis ◽  
Structure Activity ◽  
Relationship Of

Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure–activity relationship of this important class of hedgehog-pathway inhibitors.

Design, Structure–Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990

2014 ◽  
Vol 57 (21) ◽  
pp. 9124-9129 ◽  
Author(s):  
Christopher M. McBride ◽  
Barry Levine ◽  
Yi Xia ◽  
Cornelia Bellamacina ◽  
Timothy Machajewski ◽  
...  
Keyword(s):  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Design Structure ◽  
In Vivo Characterization

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 Structure-Activity Relationship and Characterization of Novel Influenza Inhibitors

2018 ◽  
Vol 114 (3) ◽  
pp. 419a
Author(s):  
Gregory Mohl ◽  
Nathan Liddle ◽  
David Michaelis ◽  
David Busath
Keyword(s):  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity

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.

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