Repurposing the inhibitors of MMP-9 and SGLT-2 against ubiquitin specific protease 30 in Parkinson’s disease: computational modelling studies

Abstract

Ubiquitin specific protease 30 (USP30) has been attributed to mitochondrial dysfunction and impediment of mitophagy in Parkinson’s disease (PD). This happens once ubiquitin that supposed to bind with deformed mitochondria at the insistence of Parkin, it’s been recruited by USP30 via the distal ubiquitin binding domain. This is a challenge when PINK1 and Parkin loss their functions due to mutation. Although, there are reports on USP30s’ inhibitors but no study on the repurposing of inhibitors approved against MMP-9 and SGLT-2 as potential inhibitors of USP30 in PD. Thus, the highlight therein, is to repurpose approved inhibitors of MMP-9 and SGLT-2 against USP30 in PD using extensive computational modelling framework. 3D structures of Ligands and USP30 were obtained from PubChem and protein database (PDB) servers respectively, and were subjected to molecular docking, ADMET evaluation, DFT calculation, molecular dynamics simulation (MDS) and free energy calculations. Out of the 18 drugs, 2 drugs showed good binding affinity to the distal ubiquitin binding domain, moderate pharmacokinetic properties and good stability. The findings showed canagliflozin and empagliflozin as potential inhibitors of USP30. Thus, we present these drugs as repurposing candidates for the treatment of PD. However, the findings in this current study needs to be validated experimentally.

Communicated by Ramaswamy H. Sarma

Keywords:

• USP30
• computational modelling
• repurposing
• MMP-9 inhibitors
• SGLT-2 inhibitors
• Parkinson’s disease

Acknowledgement

The authors thank the University of Groningen peregrine for providing computational resources to run MD simulation. All authors acknowledge their respective institutions for providing an enabling environment for learning and research. Also, all authors are thankful to Dr. Tariq, the Head of National Data Management Office, Saudi Arabia for his ongoing support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contributions

MMA and HIU: Conceptualization, Software. AUD, MK Alshammari, MK Alghazwni, and ROB: Methodology, Data curation, Writing- Original draft preparation. AUD, AMA, ROB, and OMA: Visualization, Investigation. HIU and MMA: Supervision. AUD, AMA and ROB: Software, Validation. MK Alshammari, MK Alghazwni, MMA, and OMA: Writing- Reviewing and Editing. All the authors read and approved the final version for submission.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.