IN-SILICO DEVELOPMENT OF EFFICIENT L-ASPARAGINASE ENZYME FOR ACUTE LYMPHOBLASTIC LEUKAEMIA THERAPY

L-asparaginase has been accepted clinically as an anti-tumour agent for the effective treatment of acute lymphoblastic leukaemia and lymphosarcoma. This enzyme also possesses L-glutaminase activity and causes immunological problems. Hence, efforts have been made to develop mutants with lower or no glutaminase activity. In the present study, a homology model of L-asparaginase obtained from Pectobacterium carotovorum was docked and compared with its mutants for activities, analysed for molecular dynamics and structural stability. A total of five in-silico mutants were developed using single amino acid mutagenesis and evaluated for ligand binding for both L-asparagine and L-glutamine. One of the mutants, Y306L, showed -5.89 and -5.04 while the wild L-asparaginase revealed -5.50 and -5.12 binding energies for L-asparagine and L-glutamine, respectively. Further, substrate-enzyme interaction analysis indicated that the wild L-asparaginase showed five interactions for L-asparagine as well as for L-glutamine, whereas, the mutant, Y306L depicted eight and three interactions for L-asparagine and L-glutamine. Molecular dynamics analysis denoted that mutant protein is more stable in RMSD, RMSF and radius of gyration to that of wild-type protein. Higher binding affinity was noticed with L-asparagine and lower with L-glutamine along with higher interactions with L-asparagine and lower with L-glutamine in mutant Y306L, compared to wild L-asparaginase. This suggests that this could be a possible potential candidate for the treatment of Acute Lymphoblastic Leukaemia (ALL) with less induced side effects.