Targeting Glucose Metabolism in Diabetes-A Homology Modeling and Active Site Identification for Inositol Monophosphatase

Abstract

Diabetes is a degenerative disease caused by either the body’s inability to use insulin adequately or the pancreas’s failure to release enough insulin. Diabetes is a glucose metabolic imbalance produced by the phosphodiesterase family of protein inositol monophosphatase (IMPase). Inositol monophosphatase, an enzyme involved in the phosphatidylinositol signalling pathway, is encoded by the IMPA1 gene. Homology Modelling is used to create a 3D model of the IMPA1 protein (target). The FASTA sequence for the IMPase protein (265 amino acids) (Uniprot ID H0YBL1) is obtained from the Uniprot server. Jpred, and NCBI Blast servers are used to search for templates. Based on the query coverage (92%) and Escore, the protein with the PDB ID1IMA is identified as a potential template. The structural alignment (by ClustalW) submitted to the SWISSMODEL service yields a 3D model. The Swiss PDB viewer is used to minimise energy (E =  10099.60 kcal/mole). Procheck, ERRAT, and the VERIFY 3D server validate the model. The Ramachandran plot of the 3D model indicates that 93.5% of the amino acids are in the allowed region and none are in the forbidden region. The ERRAT result shows an overall quality factor of up to 96.17% for nonbonded atomic interactions. According to NCBI blast, the conserved domain is between 60  245 amino acids. The servers (ACTIVE SITE FINDER,) indicate binding pockets in the hydrophobic area, and Swiss dock is used to determine the active residues by protein small ligand (Natural substrate, Fructose Biphosphatase FBPase receptor ) docking to identify the active site residues (Asp 90 and Thr 95) based on visualisations and a Swiss energy value. The glucose metabolism can be stopped by blocking these residues.