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Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDEδ Inhibitors
Ramin Ekhteiari Salmas1, Mert Mestanoglu2, Mine Yurtsever1
1Department of Chemistry, Istanbul Technical University, Istanbul, Turkey.
Abstract:
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.
Insights
Phosphodiesterase delta (PDEδ) inhibitors show promise for cancer drug development by blocking RAS signaling. This study reveals their mechanisms and screens them for potential cardiac side effects.
Area of Science:
- Biochemistry and Molecular Pharmacology
- Computational Drug Discovery
Background:
- Phosphodiesterase delta (PDEδ) regulates RAS subfamily protein trafficking, making it a key target in oncological drug development.
- Inhibition of PDEδ disrupts the initiation of RAS signaling pathways implicated in cancer.
Purpose of the Study:
- To investigate the mechanisms of action for novel PDEδ inhibitors using computational methods.
- To provide atomic-scale insights into PDEδ inhibition for guiding future drug design.
- To screen identified PDEδ inhibitors for potential off-target interactions with the hERG1 channel.
Main Methods:
- Utilized solved X-ray structures of inhibitor-bound PDEδ targets.
- Performed six independent all-atom molecular dynamics (MD) simulations.
- Combined MD simulations with molecular mechanics-Poisson-Boltzmann/generalized Born surface area (MM-PBSA/GBSA) calculations.
- Conducted in silico screening of PDEδ inhibitors against the hERG1 potassium channel.
Main Results:
- Identified specific mechanisms of action for a panel of novel PDEδ inhibitors.
- Provided a detailed atomic-level understanding of PDEδ inhibition.
- Assessed the in silico safety profile of the inhibitors concerning hERG1 channel interactions.
Conclusions:
- The study offers novel insights into PDEδ inhibitor mechanisms, aiding in the rational design of more effective anti-cancer drugs.
- The computational approach provides a foundation for developing targeted therapies with potentially reduced cardiac side effects.
