Multiple and Single Binding Modes of Fragment-Like Kinase Inhibitors Revealed by Molecular Modeling, Residue Type-Selective Protonation, and Nuclear Overhauser Effects

2008 ◽  
Vol 51 (19) ◽  
pp. 6225-6229 ◽  
Author(s):  
Keith L. Constantine ◽  
Luciano Mueller ◽  
William J. Metzler ◽  
Patricia A. McDonnell ◽  
Gordon Todderud ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Residue Type ◽  
Nuclear Overhauser ◽  
Nuclear Overhauser Effects

Approach in improving potency and selectivity of kinase inhibitors: Allosteric kinase inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Shangfei Wei ◽  
Tianming Zhao ◽  
Jie Wang ◽  
Xin Zhai
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Allosteric Inhibitors ◽  
Wide Range ◽  
Allosteric Sites ◽  
Protein Functions ◽  
Regulate Protein

: Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structureactivity relationships, ligand-protein interactions and in vitro and in vivo activity. Additionally, challenges as well as opportunities are presented.

scholarly journals Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2174 ◽  
Author(s):  
Annalisa Maruca ◽  
Delia Lanzillotta ◽  
Roberta Rocca ◽  
Antonio Lupia ◽  
Giosuè Costa ◽  
...  
Keyword(s):  
Essential Oils ◽  
Binding Affinity ◽  
Structural Changes ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Data Bank ◽  
Binding Modes ◽  
Starting Point ◽  
Target Action ◽  
Potential Resource

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.

Design, synthesis and molecular modeling of new quinazolin-4(3H)-one based VEGFR-2 kinase inhibitors for potential anticancer evaluation

2021 ◽  
Vol 109 ◽  
pp. 104695
Author(s):  
Abdallah E. Abdallah ◽  
Sally I. Eissa ◽  
Maged Mohammed Saleh Al Ward ◽  
Reda R. Mabrouk ◽  
Ahmed B.M. Mehany ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Kinase Inhibitors ◽  
Design Synthesis

scholarly journals NMR solution conformation of heparin-derived tetrasaccharide

1996 ◽  
Vol 318 (1) ◽  
pp. 93-102 ◽  
Author(s):  
Dmitri MIKHAILOV ◽  
Kevin H. MAYO ◽  
Ioncho R. VLAHOV ◽  
Toshihiko TOIDA ◽  
Azra PERVIN ◽  
...  
Keyword(s):  
Chair Conformation ◽  
Coupling Constants ◽  
Solution Conformation ◽  
1H And 13C Nmr ◽  
Small Deviations ◽  
J Coupling Constants ◽  
Nuclear Overhauser ◽  
Nuclear Overhauser Effects ◽  
Dynamics Simulations ◽  
Ring Conformations

The solution conformation of the homogeneous, heparin-derived tetrasaccharide ΔUA2S(1 → 4)-α-d-GlcNpS6S(1 → 4)-α-l-IdoAp2S(1 → 4)-α-d-GlcNpS6S (residues A, B, C and D respectively, where IdoA is iduronic acid) has been investigated by using 1H- and 13C-NMR. Ring conformations have been defined by J-coupling constants and inter-proton nuclear Overhauser effects (NOEs), and the orientation of one ring with respect to the other has been defined by inter-ring NOEs. NOE-based conformational modelling has been done by using the iterative relaxation matrix approach (IRMA), restrained molecular dynamics simulations and energy minimization to refine structures and to distinguish between minor structural differences and equilibria between various ring forms. Both glucosamine residues B and D are in the 4C1 chair conformation. The 6-O-sulphate group is oriented in the gauche–trans configuration in the D ring, whereas in the B ring the gauche–gauche rotomer predominates. Uronate (A) and iduronate (C) residues are mostly represented by 1H2 and 2S0 twisted boat forms, respectively, with small deviations in expected coupling constants and NOEs suggesting minor contributions from other A and C ring conformations.

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.

Structure assignment of some 3,4′-diquinolinyl sulfides studied by Nuclear Overhauser Effects, X-ray analysis and reactions with sodium methoxide

2010 ◽  
Vol 109 (10) ◽  
pp. 509-514 ◽  
Author(s):  
Stanislaw Boryczka ◽  
Andrzej Maślankiewicz ◽  
Miroslaw Wyszomirski ◽  
Teresa Borowiak ◽  
Maciej Kubicki
Keyword(s):  
Sodium Methoxide ◽  
X Ray ◽  
Nuclear Overhauser ◽  
Nuclear Overhauser Effects ◽  
Structure Assignment
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