Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2

Autor: Vertika Gautam, Vannajan Sanghiran Lee, Sharifuddin M. Zain, Noorsaadah Abd Rahman, Piyarat Nimmanpipug
Jazyk: angličtina
Rok vydání: 2021
Předmět:
MAPK/ERK pathway
Ankyrins
Protein Conformation
alpha-Helical
MAP Kinase Signaling System
Pharmaceutical Science
Organic chemistry
Molecular Dynamics Simulation
Ligands
Article
Analytical Chemistry
03 medical and health sciences
Molecular dynamics
extracellular regulated kinase
0302 clinical medicine
QD241-441
Neoplasms
Drug Discovery
MAESTRO
Extracellular
Humans
Physical and Theoretical Chemistry
Phosphorylation
Protein kinase A
Protein Kinase Inhibitors
030304 developmental biology
Mitogen-Activated Protein Kinase 1
0303 health sciences
Mitogen-Activated Protein Kinase 3
Kinase
Chemistry
Protein Stability
DARPins
Hydrogen Bonding
molecular dynamics simulations
Cell biology
Signalling
DARPin
Chemistry (miscellaneous)
030220 oncology & carcinogenesis
Drug Design
Mutation
Molecular Medicine
Algorithms
Protein Binding
Zdroj: Molecules, Vol 26, Iss 4540, p 4540 (2021)
Molecules
Volume 26
Issue 15
ISSN: 1420-3049
Popis: Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins—designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2–DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala → Asp and Ser → Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions.
Databáze: OpenAIRE
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