Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDEδ Inhibitors.
PDEδ is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDEδ targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDEδ inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDEδ protein. A detailed atomic-scale understanding of the molecular mechanism of PDEδ inhibition may assist in the design of novel PDEδ inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDEδ inhibitors are also screened in silico at the central cavities of hERG1 potassium channels.
Department of Chemistry, Istanbul Technical University, Istanbul, Turkey.
Ramin Ekhteiari
RE
Salmas
School of Medicine, Bahcesehir University, Istanbul, Turkey.
Mert
M
Mestanoglu
Department of Chemistry, Istanbul Technical University, Istanbul, Turkey.
Mine
M
Yurtsever
Centre for Molecular Simulation, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Sergei Y
SY
Noskov
Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey. Electronic address: serdar.durdagi@bahcesehir.edu.tr.
Serdar
S
Durdagi
D001665:Binding Sites; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
D010726:Phosphodiesterase Inhibitors; D014867:Water; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6