Phenothiazine as novel human superoxide dismutase modulators: discovery, optimization, and biological evaluation

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Superoxide dismutases (SODs) are crucial antioxidants protecting cells from oxidative stress.
• Identifying novel compounds to modulate human SOD activity is an active research area.

Purpose of the Study:

• To discover new human copper-zinc superoxide dismutase 1 (SOD1) modulators using a structure-based drug design approach.
• To identify novel activator/inhibitor scaffolds for SOD1 based on Plasmodium falciparum iron SOD inhibitors.

Main Methods:

• Utilized induced fit docking and molecular dynamics (MD) protocols for structure-based drug design.
• Performed structure simplification and similarity searches on identified compounds.
• Investigated SOD1 activity modulation using specific phenothiazine derivatives (trifluoperazine, chlorpromazine).

Main Results:

• Identified a phenothiazine-related scaffold as a promising SOD1 modulator.
• Observed increased SOD1 activity with trifluoperazine and decreased activity with chlorpromazine.
• MD simulations revealed distinct mechanisms for trifluoperazine (stabilizing loop) and chlorpromazine (disrupting active site interaction).

Conclusions:

• The study successfully identified potential SOD1 activators and inhibitors based on phenothiazine derivatives.
• Mechanistic insights into SOD1 modulation by trifluoperazine and chlorpromazine were elucidated.
• The findings provide a foundation for developing new therapeutic agents targeting oxidative stress-related conditions.