Steered molecular dynamics simulations for uncovering the molecular mechanisms of drug dissociation and for drug screening: A test on the focal adhesion kinase

2018 ◽  
Vol 39 (19) ◽  
pp. 1307-1318 ◽  
Author(s):  
Chung F. Wong
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Drug Screening ◽  
Molecular Mechanisms ◽  
Steered Molecular Dynamics ◽  
Dynamics Simulations

scholarly journals Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 74
Author(s):  
Justin Spiriti ◽  
Chung F. Wong
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Early Stage ◽  
Steered Molecular Dynamics ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Dissociation Kinetics ◽  
Binding Characteristics

Most early-stage drug discovery projects focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. Since many approved drugs have nonequilibrium binding characteristics, there has been increasing interest in optimizing binding kinetics early in the drug discovery process. As focal adhesion kinase (FAK) is an important drug target, we examine whether steered molecular dynamics (SMD) can be useful for identifying drug candidates with the desired drug-binding kinetics. In simulating the dissociation of 14 ligands from FAK, we find an empirical power–law relationship between the simulated time needed for ligand unbinding and the experimental rate constant for dissociation, with a strong correlation depending on the SMD force used. To improve predictions, we further develop regression models connecting experimental dissociation rate with various structural and energetic quantities derived from the simulations. These models can be used to predict dissociation rates from FAK for related compounds.

scholarly journals Molecular dynamics simulations of mechanical failure in polymorphic arrangements of amyloid fibrils containing structural defects

2013 ◽  
Vol 4 ◽  
pp. 429-440 ◽  
Author(s):  
Hlengisizwe Ndlovu ◽  
Alison E Ashcroft ◽  
Sheena E Radford ◽  
Sarah A Harris
Keyword(s):  
Mechanical Properties ◽  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Steered Molecular Dynamics ◽  
Mechanical Failure ◽  
Structural Defects ◽  
Dynamics Simulations

We examine how the different steric packing arrangements found in amyloid fibril polymorphs can modulate their mechanical properties using steered molecular dynamics simulations. Our calculations demonstrate that for fibrils containing structural defects, their ability to resist force in a particular direction can be dominated by both the number and molecular details of the defects that are present. The simulations thereby suggest a hierarchy of factors that govern the mechanical resilience of fibrils, and illustrate the general principles that must be considered when quantifying the mechanical properties of amyloid fibres containing defects.

‘Piperazining’ the catalytic gatekeepers: unraveling the pan-inhibition of SRC kinases; LYN, FYN and BLK by masitinib

2019 ◽  
Vol 11 (18) ◽  
pp. 2365-2380
Author(s):  
Aimen K Aljoundi ◽  
Clement Agoni ◽  
Fisayo A Olotu ◽  
Mahmoud ES Soliman
Keyword(s):  
Molecular Dynamics ◽  
B Cell ◽  
Molecular Dynamics Simulations ◽  
Molecular Mechanisms ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Dynamics Simulation ◽  
Large B Cell Lymphoma ◽  
Dynamics Simulations ◽  
Large B Cell

Aim: Blocking oncogenic signaling of B-cell receptor (BCR) has been explored as a viable strategy in the treatment of diffuse large B-cell lymphoma. Masitinib is shown to multitarget LYN, FYN and BLK kinases that propagate BCR signals to downstream effectors. However, the molecular mechanisms of its selectivity and pan-inhibition remain elusive. Materials & methods: This study therefore employed molecular dynamics simulations coupled with advanced post-molecular dynamics simulation techniques to unravel the structural mechanisms that inform the reported multitargeting ability of masitinib. Results: Molecular dynamics simulations revealed initial selective targeting of catalytic residues (Asp334/Glu335 – LYN; Asp130/Asp148/Glu54 – FYN; Asp89 – BLK) by masitinib, with high-affinity interactions via its piperazine ring at the entrance of the ATP-binding pockets, before systematic access into the hydrophobic deep pocket grooves. Conclusion: Identification of these ‘gatekeeper’ residues could open up a novel paradigm of structure-based design of highly selective pan-inhibitors of BCR signaling in the treatment of diffuse large B-cell lymphoma.

The talin–integrin interface under mechanical stress

2014 ◽  
Vol 10 (12) ◽  
pp. 3217-3228 ◽  
Author(s):  
Sampo Kukkurainen ◽  
Juha A. Määttä ◽  
John Saeger ◽  
Jarkko Valjakka ◽  
Viola Vogel ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Mechanical Stress ◽  
Steered Molecular Dynamics ◽  
Dynamics Simulations

Interactions and force resistance of different β-integrin–talin complexes were analysed in a set of steered molecular dynamics simulations.

scholarly journals Steered molecular dynamics simulations reveal the role of Ca2+ in regulating mechanostability of cellulose-binding proteins

2018 ◽  
Vol 20 (35) ◽  
pp. 22674-22680 ◽  
Author(s):  
Melissabye Gunnoo ◽  
Pierre-André Cazade ◽  
Adam Orlowski ◽  
Mateusz Chwastyk ◽  
Haipei Liu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Binding Proteins ◽  
Mechanical Stability ◽  
Binding Specificity ◽  
Steered Molecular Dynamics ◽  
Dynamics Simulations ◽  
Cellulose Binding ◽  
High Mechanical Stability

Cellulosome nanomachines utilise binding specificity and high mechanical stability in breaking down cellulose.

How strong are hydrogen bonds in the peptide model?

2020 ◽  
Vol 22 (3) ◽  
pp. 1392-1399
Author(s):  
Jakub Dąbrowski ◽  
Wiesław Nowak ◽  
Arkadiusz Ptak
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonds ◽  
Molecular Dynamics Simulations ◽  
Force Spectroscopy ◽  
Steered Molecular Dynamics ◽  
Dynamic Force ◽  
Dynamic Force Spectroscopy ◽  
Dynamics Simulations

We provide a methodology based on the steered molecular dynamics simulations and dynamic force spectroscopy calculations to determine the kinetic and energetic characteristics of hydrogen bonds.

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