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

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

Automated summary

Ubiquitin specific protease 30 (USP30) has been identified as a key player in mitochondrial dysfunction and impaired mitophagy in Parkinson's disease (PD). By recruiting ubiquitin that is supposed to bind with damaged mitochondria, USP30 poses a challenge when PINK1 and Parkin lose their functions. This study aims to repurpose approved inhibitors of MMP-9 and SGLT-2 as potential inhibitors of USP30 in PD through computational modeling. The findings suggest canagliflozin and empagliflozin as promising candidates for the treatment of PD. However, further experimental validation is needed.