Proof of concept for poor inhibitor binding and efficient formation of covalent adducts of KRASG12C and ARS compounds

2020 ◽  
Vol 18 (16) ◽  
pp. 3069-3081 ◽  
Author(s):  
Maria G. Khrenova ◽  
Anna M. Kulakova ◽  
Alexander V. Nemukhin
Keyword(s):  
Molecular Modeling ◽  
Kinetic Analysis ◽  
Proof Of Concept ◽  
Inhibitor Binding ◽  
Covalent Adducts ◽  
Kras Protein

Comprehensive molecular modeling and kinetic analysis reveal a novel mechanism of the inhibition of the oncogenic mutant of the “undruggable” KRAS protein.

Molecular modeling study for conformational changes of Sirtuin 2 due to substrate and inhibitor binding

2012 ◽  
Vol 30 (3) ◽  
pp. 235-254 ◽  
Author(s):  
Sugunadevi Sakkiah ◽  
Meganathan Chandrasekaran ◽  
Yuno Lee ◽  
Songmi Kim ◽  
Keun Woo Lee
Keyword(s):  
Molecular Modeling ◽  
Conformational Changes ◽  
Inhibitor Binding ◽  
Molecular Modeling Study ◽  
Modeling Study

scholarly journals Effect of Heldanamycin Binding on the Thr90 Phosphorylation Site of Hsp90

2021 ◽  
Vol 4 (3) ◽  
pp. e00145
Author(s):  
K.A. Shcherbakov ◽  
D.S. Shcherbinin ◽  
A.V. Veselovsky
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Androgen Receptor ◽  
Molecular Modeling ◽  
Phosphorylation Site ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Inhibitor Binding ◽  
Atp Binding Site ◽  
Modeling Methods

Prostate cancer is hormone-dependent and the androgen receptor (AR) is involved in its development. AR is a transcription factor that is activated by ligand binding, result in its translocation into the nucleus, where it initiates gene transcription. In an inactive state in cytoplasm AR exists as a complex with heat shock protein 90 (HSP90) and some other proteins. When the agonist binds, a conformational change in AR occurs, resulting in HSP90 and other chaperones dissociating. Recently it has been shown that for the dissociation of the HSP90-AR complex and the translocation of the latter into the nucleus, phosphorylation of the Thr-90 residue of the N-terminal domain of HSP90 is necessary. In this work, the effect of the HSP90 inhibitor, heldanamycin, interacting with the ATP-binding site, on the Thr90 phosphorylation site was investigated by molecular modeling methods. It has been shown that inhibitor binding slightly affects the size and mobility of cavity around Thr90. It is suggested that inhibitor binding to HSP90 does not result in changing the protein structure and does not influence on protein phosphorylation, and partially explains low effectiveness of such type of drugs in the therapy of prostate cancer.

scholarly journals Use of Crystallography and Molecular Modeling for the Inhibition of the Botulinum Neurotoxin A Protease

2021 ◽  
Author(s):  
Lewis Turner ◽  
Alexander Lund Nielsen ◽  
Lucy Lin ◽  
Antonio J. Campedelli ◽  
Nicholas Silvaggi ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Crystal Structures ◽  
Botulinum Neurotoxin ◽  
Enzyme Inhibitor ◽  
Binding Modes ◽  
Botulinum Neurotoxin A ◽  
Inhibitor Binding

We have used crystal structures and molecular modeling to evaluate inhibitor binding modes and design a series of compounds to take advantage of a new, cryptic, hydrophobic sub-pocket. This is a classical SBDD approach to improving enzyme/inhibitor interactions.

Molecular modeling of Plasmodium falciparum peptide deformylase and structure-based pharmacophore screening for inhibitors

RSC Advances ◽  
2016 ◽  
Vol 6 (35) ◽  
pp. 29466-29485 ◽  
Author(s):  
Anu Manhas ◽  
Sivakumar Prasanth Kumar ◽  
Prakash Chandra Jha
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Modeling ◽  
Design Strategy ◽  
Peptide Deformylase ◽  
Metal Coordination ◽  
Coordination Geometry ◽  
Inhibitor Design ◽  
Inhibitor Binding ◽  
Pharmacophore Screening

The role of metal coordination geometry and actinonin (inhibitor) binding was examined to develop pharmacophore-based inhibitor design strategy forPlasmodium falciparumpeptide deformylase.

scholarly journals Modeling the Interplay of Poor Inhibitor Binding and Efficient Formation of a Covalent Adduct upon the Interaction of ARS Compounds with KRASᴳ¹²ᶜ

2019 ◽  
Author(s):  
Maria Khrenova ◽  
Anna M. Kulakova ◽  
Alexander Nemukhin
Keyword(s):  
Reaction Mechanism ◽  
Experimental Studies ◽  
Inhibitor Binding ◽  
Modeling Tools ◽  
The Family ◽  
Covalent Adduct ◽  
Covalent Inhibitors ◽  
Kras Protein

<p>We contribute to the emerging topic of development of the family of prospective covalent inhibitors of the “undraggable” KRAS protein. Recent experimental studies on the x-ray [Nature 2013; Cell, 2016], <i>in vivo</i> [Cancer Discov., 2016] and <i>in vitro</i> [Nat. Struct. Mol. Biol., 2018] kinetics reached the top of possible detalization of the process. Although many questions on the reaction mechanism still arise. Herein we utilize a set of supercomputer molecular modeling tools and our original strategy on kinetic analysis to evaluate the reaction mechanism of protein-inhibitor interactions to clarify them. Moreover we suggest original strategy to bridge the microscopic calculated parameters with the macroscopic observed ones and compare them.</p>

scholarly journals Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase

Glycobiology ◽  
2016 ◽  
Vol 26 (6) ◽  
pp. 640-654 ◽  
Author(s):  
Daniele Pala ◽  
Silvia Rivara ◽  
Marco Mor ◽  
Ferdinando Maria Milazzo ◽  
Giuseppe Roscilli ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Kinetic Analysis ◽  
Inhibition Mechanism
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