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

Abstract

Superoxide dismutases (SODs) are regarded as important antioxidants for protecting cells against damage arising from oxidative stress. Much research is focused on finding new chemicals with an ability to boost human SOD activity. In the research described herein a structure-based approach was used to identify new human Cu-Zn superoxide dismutase (SOD1) modulators based on previously reported plasmodium falciparum iron SOD inhibitors using induced fit docking and molecular dynamic (MD) protocols. The compound with the highest docking binding energy was selected for further structure simplification followed by structural similarity and MD in order to find a new activator/inhibitor scaffold of the SOD1 enzyme. According to the docking survey of the mentioned series, 1,4-bis(3-(1,4,8-trichloro-10Hphenothiazin-10-yl) propyl) piperazine (DS88) was the top scoring compound interacting with the SOD1 active site channel. Following structure simplification and similarity search, the most promising scaffold which is closely related to the phenothiazine antipsychotic class, was identified. Compared with the normal blood SOD1 activity, the percent of O₂ production increased with trifluoperazine, while it decreased with the chlorpromazine. The molecular dynamic investigation shows that trifluoperazine exerts its SOD1 activating effect by stabilizing electrostatic loop while chlorpromazine employs SOD1 inhibition activity through repositioning of the electrostatic loop and increasing its distance from the catalytic metal site which diminished substrate specificity and catalytic activity of the SOD1 enzyme. The results identified the preferred region, orientation, and types of interaction for each activator or inhibitor compound.

Graphical Abstract

Communicated by Ramaswamy H. Sarma

Keywords:

• Human superoxide dismutase
• induced fit docking
• molecular dynamic
• activator
• phenothiazine

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contribution

This study was designed by M. A. H. A, S. F and A.A performed computational and biologic evaluation. Data was analyzed and interpreted by H. P-S. The manuscript was written by H. A., H. P-S and M. A. with input from all authors.

Additional information

Funding

We gratefully acknowledge the financial support from Research Council of Tehran University of Medical Sciences. This work has been partially funded by a grant from the Spanish Ministry of Economy and Competitiveness (CTQ2017-87974-R) and by the Fundación Séneca del Centro de Coordinación de la Investigación de la Región de Murcia under Projects 20988/PI/18 and 20524/PDC/18.