| Popis: |
Mutations in PINK1 kinase are known to be responsible for the early-onset of Parkinson's disease. The protein resides on the outer-membrane of healthy mitochondria, and acts as a quality controller by regulating and maintaining dysfunctional mitochondria also known as mitophagy. Limited knowledge of the mechanism of protein has made it cumbersome to elucidate an effective treatment. In this paper, we screen a set of kinase inhibitors using high-throughput screening for investigating potential activators. We have for the first time shown the plausible binding and selectivity towards the kinase inhibitors in the mutant PINK1 binding site. We also could highlight the ligand bind/unbinding pathway identifying the most stable binding pose utilizing the residues from the P-loop and DFG motif for drugs Tepotinib and Pyrotinib. Interestingly, no direct interaction of mutated residues with the ligand molecules were observed. Furthermore, we highlight that the Ins3 region and SER228 of the N-lobe display distinct conformational states that are inline with crystal structure for substrate binding specificity. Collectively, our findings provide a molecular basis for the PINK1 potential kinase activator, which would further facilitate as a starting point to probe new therapeutics by using the structure based drug designing for treating neurological disorder. |
